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0.625 mg Progesterone 2.5mg

0.625 mg Progesterone 2.5mg diabetes as secondary objective (table 3) [18-21]. Eight of these studies found a significant reduction in the incidence of new cases of diabetes by the renin angiotensin aldosterone system inhibitors based on fasting plasma glucose. The relative risk reduction varied between 14 and 87% with an overall mean adjusted for population of 25.6% (fig. 2).

Pravastatin and estrogen/progesterone replacement therapy are two other drugs that have also shown potential for the prevention of type-2 diabetes (fig. 2). The West of Scotland Coronary Prevention Study examined the effect of pravastatin on the development of diabetes as a secondary endpoint [22]. After a follow-up of 4.8 years, pravastatin was associated with a 30% risk reduction of diabetes (p = 0.036) [23]. The Heart and Estrogen/progestin Replacement Study [24] also examined the effect of estradiol 0.625 mg plus

Fig. 2. Pharmacological interventions and the prevention of type-2 diabetes as a secondary outcome. The histograms represent the population-adjusted mean risk reduction where there is more than one intervention trial.

medroxyprogesterone acetate 2.5 mg versus placebo on the development of diabetes over a 4-year period based on fasting plasma glucose. The hormone replacement therapy was associated with a 35% risk reduction for diabetes (p = 0.006).

All these studies are interesting and do suggest the potential benefit of these drugs in the prevention of diabetes. But as a secondary outcome, they can only be considered as generating a hypothesis and need to be confirmed in prospective studies in which the prevention of diabetes will be the primary outcome.

Conclusion

It is now established that type-2 diabetes can be prevented or delayed through a lifestyle-modification program or pharmacological intervention. Since weight reduction and exercise is difficult to maintain in the long-term, it is important to have pharmacological agents such as acarbose, metformin and probably orlistat that have been shown to be effective in reducing the risk of diabetes in high-risk populations. These can be used as an adjunct or an alternative to lifestyle modification. Bariatric surgery can also be used as an effective alternative in morbidly obese subjects to prevent diabetes.

A number of studies have suggested that other drugs, such as renin angiotensin aldosterone system inhibitors, statins and hormone replacement could also be of potential benefit for the prevention of diabetes. These, however, need to be confirmed in prospective trials. Some are currently being tested in ongoing trials. The DREAM study is testing ramipril and rosiglita-zone [14], the NAVIGATOR study nateglinide and valsartan [25], and finally,

ACT NOW is assessing pioglitazone in preventing the progression of IGT to type-2 diabetes.

With this new knowledge, strong recommendations have to be made to screen and treat IGT. These new strategies should help to attenuate the worldwide burden of diabetes.

Acknowledgement

We are grateful to Susanne Bordeleau for preparing the manuscript and illustrations.

References

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8 Yang W, Lixiang L, Jinwu Q, et al: The preventive effect of acarbose and metformin on the progression to diabetes mellitus in the IGT population: a 3-year multicenter prospective study. Chin J Endocrinol Metab 2001;17:131-136.

9 Knowler WC, Barrett-Connor E, Fowler SE, et al: Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393-403.

10 Chiasson JL, Josse RG, Gomis R, et al: Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:2072-2077.

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12 Buchanan TA, Xiang AH, Peters RK, 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;51:2796-2803.

13 Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L: XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care 2004;27:155-161.

14 Gerstein HC, Yusuf S, Holman R, et al: Rationale, design and recruitment characteristics of a large, simple international trial of diabetes prevention: the DREAM trial. Diabetologia 2004;47:1519-1527.

15 Pories WJ, Swanson MS, MacDonald KG, et al: Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus. Ann Surg 1995;222: 339-352.

16 Long SD, O'Brien K, MacDodnald KG Jr, et al: Weight loss in severely obese subjects prevents the progression of impaired glucose tolerance to type II diabetes. Diabetes Care 1994;17: 372-375.

17 Sjöstrom L, Lindroos AK, Peltonen M, et al: Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-2693.

18 Niklason A, Hedner T, Niskanen L, Lanke J: Development of diabetes is retarded by ACE inhibition in hypertensive patients - a subanalysis of the Captopril Prevention Project (CAPPP). J Hypertens 2004;22:645-652.

19 Hansson L, Lindholm LH, Ekbom T, et al: Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 1999;354:1751-1756.

20 Lindholm LH, Ibsen H, Borch-Johnsen K, et al: Risk of new-onset diabetes in the Losartan Intervention for Endpoint reduction in hypertension study. J Hypertens 2002;20:1879-1886.

21 Yusuf S, Gerstein H, Hoogwerf B, et al: Ramipril and the development of diabetes. JAMA 2001;286:1882-1885.

22 Shepherd J, Cobbe SM, Ford I, et al: Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-1307.

23 Freeman DJ, Norrie J, Sattar N, et al: Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 2001;103:357-362.

24 Hulley S, Grady D, Bush T, et al: Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605-613.

25 Scheen AJ: Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system. Drugs 2004;64:2537-2565.

26 ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial: major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-2997.

27 Vermes E, Ducharme A, Bourassa MG, et al: Enalapril reduces the incidence of diabetes in patients with chronic heart failure: insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation 2003;107:1291-1296.

28 Lindholm LH, Persson M, Alaupovic P, et al: Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE study). J Hypertens 2003;21:1563-1574.

29 Lithell H, Hansson L, Skoog I, et al: The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003;21:875-886.

30 Pfeffer MA, Swedberg K, Granger CB, et al: Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003;362:759-766.

31 Julius S, Kjeldsen SE, Weber M, et al: Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-2031.

32 Kanaya AM, Herrington D, Vittinghoff E, et al: Glycemic effects of postmenopausal hormone therapy: the Heart and Estrogen/progestin Replacement Study. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:1-9.

Discussion

Dr. Katsilambros: My compliments for this nice presentation. Please allow me a very specific question. If a close relative of yours had impaired glucose tolerance, was 50 years old, and had a body mass index (BMI) of 34, this person would then either have to change his lifestyle or take drugs. The question at this point, would you also give him drugs if he changed his lifestyle? But if this person was not willing at all to change his lifestyle towards the better, would you subscribe drugs straight from the beginning?

Dr. Chiasson: That is an interesting question and certainly a problem that we are or will be faced with. After looking at the data of the Diabetes Prevention Program (DPP), the Diabetes Prevention Study (DPS) and the Dutchen study, there is no doubt that the lifestyle modification program should be first-line treatment of pre-diabetic states. Of course if people are open to that, want to lose weight, want to exercise, I think that has to be supported through prescription as well as through counseling. However, in this population, which I would follow over time, if I see that plasma glucose starts to increase gradually despite these measures, I would consider pharmacological intervention. In Canada those are the guidelines. We are not sure what the failings are of the lifestyle modification program. Of course if we follow plasma glucose, whether it be fasting or after 75 g glucose, and it keeps increasing, then we should add drugs. Metformin and acarbose have been shown to be effective. I think the postprandial glucose is a very strong predictor of progression to diabetes. Personally I don't think that even in patients who are unwilling to change their lifestyle I would start with medication because I don't think that medication and then overindulging would be of any benefit, at least in the long-term. We all have the responsibility to be very convincing, follow the patients and encourage them to comply to a well-designed lifestyle modification program. And on top of that I would do exactly as for cooperative patients and would most likely end up adding some drugs. I think the drugs are there as an alternative, certainly in combination with lifestyle modification, although there is no study showing that this is going to be more effective. One would suspect that, but again if they operate with the same mechanism, perhaps not, we don't know.

Dr. Ditschuneit: With bariatric surgery remarkable amounts of weight loss can be achieved. The weight loss is 30% in the Swedish Obese Subjects study, and after 10 years it is still 16%. How can we explain that some of these patients, although they remain obese, will not develop diabetes after being operated? Is there a range of BMI in which the risk of diabetes is particularly low or high?

Dr. Chiasson: I will answer the second part of your question first. I don't think that bariatric surgery cures diabetes. I don't think that we have any cure for diabetes, though there is in most cases a normalization of the plasma glucose, certainly the fasting plasma glucose. However if the patients are challenged, the first phase insulin secretion still remains totally out of proportion; so the basic problem is still there. Why do they respond to this huge amount of weight loss, much more than with diet alone? My simple view on the subject is that the pancreas is still able to compensate for so much insulin resistance, and by doing that insulin resistance is decreased to a level where the P-cell can compensate for the insulin resistance. That is my simple explanation for why despite the fact that they are still obese there is a normalization of plasma glucose.

Dr. Hill: I think we have to consider the economics of all this. For example, if you performed bariatric surgery on everybody in the US who qualifies with a BMI above 40, the cost would be more than the total health care dollars spent by the US. So it is probably one reason the surgeons won't take over the world in this area. But even with drugs, xenical costs about USD 100/month. As diabetes is increasing, can you perhaps address how we can afford these kinds of approaches to its management?

Dr. Chiasson: First regarding surgery, you are right, bariatric surgery costs a lot, but it is quite well known that in the US and in Canada there has been a huge increase over the last 5 years at least for bariatric surgery. There is a large population and a huge marker for this type of approach because obesity has become a major problem. But the government, at least in Canada where we have a national medicare system, would never pay for any bariatric surgery. Regarding the economics, I have not seen economic studies done with orlistat, I know that it has been done with metformin and acarbose, and I know that for those two drugs that are on the market at the present time the cost:ben-efit ratio is positive. Even the studies that have only looked at intervention have not taken into account the long-term complications. If you add that in, then it is even more cost-effective. So yes, I think it would be cost-effective to do some prevention study. I think it would pay for the government, at least in Canada, to pay for a year at a gym rather than paying for the costs of obesity and diabetic complications in the long-term.

Dr. Hill: But then you have to get them to use the gym.

Dr. Slama: I would like to challenge the answer you gave to Dr. Katsilambros who asked you if you would give drugs to those patients who are not willing to lose weight or modify their lifestyle. You answer was you do not want them to overindulge. Do you really think that those patients who do not lose weight overindulge; do you really think that those patients who are not able to exercise regularly overindulge? Could you tell us how much the mean weight loss is in your regular patients on a large cohort; how much exercise you obtain in your cohort of patients? I don't have the results from my practice, but it is my opinion that very few patients really lose weight in the long-term. Should we not give them drug therapy just because they don't lose weight?

Dr. Chiasson: I think that is an over-interpretation of my statement. Like you, I think my success is very low, and that obesity comes from overindulging. I don't think that obesity appeared in Europe during the Second World War, so it comes from overindulging. The second thing is that the group that Dr. Katsilambros mentioned, somebody who does not want to stick to a diet, and those are usually the people who do overindulge. That is a different thing. I am not saying that I would not give them drugs; what I am saying is that in cooperative patients it very easy, they want to lose weight, and despite the fact that they don't lose much weight, they go on a diet even if they maintain their weight and do exercise a little bit more than they did, that will be beneficial. By following the plasma glucose I then decide when to start with pharmacological intervention. In the other patients I have to work harder to convince them that it is important, but I will do exactly the same thing.

Dr. Slama: Work harder but without too much hope because we know what results we can obtain. I agree of course that they are overindulging once in their life.

Dr. Chiasson: That is true, but if you put diabetics on a diet and follow them, even if they don't lose weight the blood sugar will come down. Most of the time it is because they have better eating habits even if they don't lose weight. That in itself, and I strongly believe in the postprandial plasma glucose. I strongly believe that if the diet is just modified, and I will not talk about glycemic index or fibers but I think they should be part of the diet, if the postprandial plasma glucose is reduced, I think just there a long-term beneficial effect should be seen, even if the patient doesn't lose weight, but if the plasma glucose is followed it should tell you when to start drug intervention.

Dr. Slama: So on this point we agree. But you cannot link your prescription to the results obtained beforehand on lifestyle modification. Of course you only need to prescribe drugs for those people exhibiting some adherence to your principles, trying their best whatever the results, and when you are convinced that they are trying their best.

Dr. Chiasson: Yes, as I said how do you define diet? I think that is a problem. This being said, I think that the plasma glucose should dictate the prescription.

Ms. Franz: Your earlier comment that people with diabetes have improved blood glucose levels even without weight loss because of better eating habits is of interest. It has been suggested that a reduced energy intake is more important than weight loss for improving insulin resistance [1]. Do you think the reduction in diabetes in subjects undergoing bariatric surgery is just as likely from their reduced food intake as it is from their weight loss?

Dr. Chiasson: Definitely they eat a lot less because they have a small stomach. One of the problems is that in most of the studies the metabolic assessment has not been done properly, and that is a major problem. Very often we don't have a good evaluation beforehand and we don't have a good follow-up after bariatric surgery. But now there are some very interesting things being done using laparoscopy; the ileum is being changed and put right after the stomach. There are a lot of interesting things being done, but again that would still remain for a morbidly obese population.

Dr. Halimi: I have two questions. First in contrast to the lifestyle intervention in the DPP study and the Study to Prevent NIDDM, do you think that metformin and acarbose do not prevent diabetes, but represent an early treatment of type 2? Second with regard to acarbose, do you think that it could be an indirect effect via gut factors?

Dr. Chiasson: I didn't want to get involved in this discussion as to whether it is treatment or prevention of diabetes. Of course it is a good question and I don't think we can answer it. Certain drugs are being tested and it is going to be very difficult. Metformin and thiazolidinediones (TZDs) have long-term effects; it takes 2-3 months to have a maximum effect, and I presume it takes 2-3 months to see the effect disappear. So it will be difficult unless the patients are followed over time to tell whether the disease is being treated or prevented. With acarbose it is different because acarbose is not absorbed, it decreases the postprandial, that is the main effect. It does not have any impact on the oral glucose tolerance test. The oral glucose tolerance test still remains a valid diagnostic tool. We all know that acarbose and all the a-glucose inhibitors increase GLIT-1, but whether that has an impact on prevention, we don't know; whether it has an impact on reducing the emptying of the stomach, we don't know. It would be very difficult to study that with acarbose. I doubt very much that it has an effect on the regeneration of the p-cell. It is an interesting concept; I think it works in rats, but I don't think it works in humans. I have seen data in rats with a-glucosidase inhibitors that show exactly the same regeneration of the p-cell as TZD. So one has to be very careful in interpreting the data from rat to human. There are still lots of open questions; there are other factors, gut factors, short chain fatty acid and all this kind of thing that could be involved, but we don't have the answer yet. But independent of all that, whether we treat early diabetes or prevent diabetes, if we delay the complications by 5 or 10 years that will reduce the burden on the health care system.

Dr. Jialun Chen: Thank you very much for your comprehensive review. You mentioned the TRIPOD study, and we now know that there are two other studies with troglitazone. The duration of the intervention is only 10 months. Compared with the placebo group there was a risk reduction of diabetes of 75%. The subgroup study from Denver and Philadelphia continued the DPP study. They have completed the study after 3 years and the risk reduction was 88%. It is very impressive, and I would like to know your opinion about this issue.

Dr. Chiasson: I am not familiar with the TZD study. The only studies that I am aware of are the DREAM study, in which I am participating, and the Fronso study which is ongoing at the present time. But so far we don't have any data from those studies. There was also the Proactive study which is a study in diabetes. In the DPP, and you will correct me if I am wrong, the troglitazone arm was very effective, it had a 75% risk reduction when the drug was discontinued. But when the drug was tested later on, it went back up to the incidence equivalent to the control group. The TRIPOD study, in which Buchanan tried to make a big thing about the prolonged effect of troglitazone, was based on 6 events and to me 6 events can fall anywhere over an 8-month period. So I think that most of the drugs as well as the non-pharmacological interventions only work if they are followed them or if you take them.

Reference

1 Assali AR, Ganor A, Beigel Y, et al: Insulin resistance in obesity: body-weight or energy balance? J Endocrinol 2001;171:293-298.

Glycemic Effect of Carbohydrates

Bantle JP, Slama G (eds): Nutritional Management of Diabetes Mellitus and Dysmetabolic Syndrome. Nestlé Nutr Workshop Ser Clin Perform Program, vol 11, pp 43-56, Nestec Ltd., Vevey/S. Karger AG, Basel, © 2006.

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