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A 45-year-old African American man with a history of obesity and hypercholesteremia has been under your care for the past three years. He has a family history of both T2DM (type 2 diabetes mellitus) and cardiovascular disease but no history of cardiovascular events.
He reports no cardiac symptoms and no polyuria, polydypsia, or fatigue.
About a year ago, the patient requested blood glucose screening because his brother had just been diagnosed with T2DM. At that time, his HbA1c (glycated hemoglobin) level was 5.8%. You recommended weight loss and exercise of 30 minutes daily. The patient reports intermittent success with weight loss, but has been unable to sustain it. He reports attempting to walk most days, but notes that work and family obligations as well as inclement weather often make this impossible.
The patient’s HbA1c has risen to 6.3% since you last examined him, an increase of 0.5%, and a recent blood glucose test showed an FPG (fasting plasma glucose) of 115 mg/dL. He has also gained 4 pounds, resulting in an increase in BMI (body-mass index) from 31 to 32 kg/m2 over the past year.
His hypercholesteremia is treated with simvastatin (20 mg daily). He also takes aspirin (81 mg daily). He reports taking these medications consistently. With medication, his LDL (low-density lipoprotein) is at goal; whereas his HDL (high-density lipoprotein) and triglycerides are 35 mg/dL and197 mg/dL respectively. Additional lab tests show normal renal and liver function, including a Cr (serum creatinine) of 0.9 mg/dL, a SGOT (serum glutamic oxaloacetic transaminase) of 36 mg/dL, and a SGPT (serum glutamic pyruvic transaminase) of 42 md/dL. His TFTs (thyroid function tests) are also normal.
Physical examination shows normal cardiorespiratory, abdominal, and neurologic findings. His blood pressure is normal (128/78 mmHg). The patient shows acanthosis nigricans behind his neck.
The patient seeks advice on how to manage his situation to prevent T2DM.
Treatment Options
Which one of the following treatment options, any one of which could be considered correct, do you think would be most appropriate for this patient?
1. Reinforce lifestyle changes
2. Reinforce lifestyle changes plus initiate metformin
3. Reinforce lifestyle changes plus initiate TZDs
Continue to Management Options
Lifestyle Modification
Doron Schneider, MD
Abington Memorial Hospital
Abington, PA
Understanding what is possible from lifestyle modification could allow patients such as the one depicted in this case study to delay, or potentially avoid, medication therapy. Several published studies have demonstrated that lifestyle modification can delay the progression from pre-diabetes to diabetes and, importantly, enhance beta cell function in a robust way. However, generalizing these highly controlled studies, which provided pre-diabetic patients with ample supports to assist adherence to lifestyle changes, to patients seen in the average primary care practice will require practice redesign and knowledge of other available community supports.
Benefits of Lifestyle Change in Preventing Diabetes
Several studies have demonstrated the benefit of lifestyle change in reducing diabetes risk. The Diabetes Prevention Program (DPP), for example, randomized patients with impaired glucose tolerance (IGT) to intensive lifestyle modification, metformin therapy, or placebo.[1] The lifestyle modification group was more successful than the metformin group in reducing new onset diabetes, with risks dropping by 58% in the lifestyle group and 31% in the metformin group. The rate of progression to diabetes was 5%, 7.8% and 11% for the lifestyle, metformin, and placebo groups respectively, with lifestyle modification most effective for patients over 60 years of age. The lifestyle group underwent intensive individual counseling and coaching in over 16 sessions aimed at a variety of issues such as goal setting, overcoming barriers, motivation, problem solving, self monitoring, calorie counting, healthy eating, stress management, understanding and social cues. These resources are available to the public at http://www.bsc.gwu.edu/dpp/lifestyle/dpp_part.html.
Assuming adequate adherence, Markov simulation modeling predicts that DPP interventions can delay diabetes onset by approximately 11 years. In addition, it shows the cost-effectiveness of the program’s lifestyle modifications, with cost per quality–adjusted life year (QALY) estimated at approximately $1,100 for the lifestyle versus $31,300 for the metformin intervention.[2]
The 2001 Finnish Diabetes Prevention Study (DPS) also demonstrated that lifestyle changes can reduce new onset diabetes in overweight patients with IGT. Patients randomized to lifestyle changes (including individualized counseling on nutrition and exercise) experienced a 58% reduction of new onset diabetes mellitus compared to controls over the seven year study period (4.3 versus 7.4 cases per 100 years).[3] Similarly, the Da Qing Diabetes Prevention trial randomized 577 patients with IGT from China to control, diet, exercise, or diet plus exercise. Compared with the control group those in the combined diet and exercise group had a 51% lower annual incidence of diabetes during the six-year active intervention period (7% vs. 11%) and 43% lower cumulative incidence in 20-year follow-up (80% vs. 93%). The intervention group spent an average of 3.6 fewer years with diabetes. Interestingly, however, there was no significant difference in cardiovascular disease-related mortality between subgroups.[4]
Finally, several studies have specifically associated adherence to a Mediterranean diet (defined as one rich in olive oils, legumes, unrefined cereals, fruits, and fish, plus low consumption of meat and meat products, and moderate wine consumption) with a reduced risk of diabetes. A prospective cohort trial of healthy Spanish patients,[5] for example, demonstrated up to 83% reduction in risk of new onset diabetes, while a recent meta-analysis has linked numerous other positive health effects such as a total reduction in mortality, cardiovascular diseases, and incidence of cancer as well as Parkinson’s and Alzheimer’s disease to this diet.[6]
Lifestyle Change and Improved Beta Cell Function
Numerous studies have demonstrated improved beta cell function after lifestyle modification, both in obese and in otherwise healthy patients with type 2 diabetes. One study documented improved beta cell function after lifestyle-mediated weight loss in obese patients older than 65 years of age.[7] Evolving literature suggests that the incretin effect may mediate enhanced insulin secretion in obese patients following lifestyle modification.[8]
In another study involving male patients with uncomplicated type 2 diabetes who underwent three months of training (ergometric cycling), beta cell responses improved in patients who were “moderate” insulin secretors (as defined by c-peptide responses to intravenous glucagon and arginine) at baseline. Significantly, patients originally defined as “low secretors” did not improve after lifestyle modification, highlighting the need for aggressive lifestyle modification as early as possible, i.e., while beta cell reserve remains.[9]
The Physicians’ Role
While the patient in this case study has been advised to lose weight before, he has thus far been unsuccessful. To increase likelihood of success, it is worth considering that weight loss requires patients to 1) make a commitment; 2) get emotional support--often accomplished by involving family or friends in setting and working together towards a goal; 3) set realistic, incremental goals--five pounds at a time! Short term goals are easier to achieve and seem less overwhelming; 4) count calories--increasing awareness and tracking of caloric intake, combined with a search for a 250 calorie a day reduction (either through portion control or substitutions) can lead to a half a pound a week of weight loss; 5) increase activity--encouraging patients to make simple lifestyle changes such as taking stairs, parking farther away from stores, walking during lunch breaks, etc. can lead to manageable, meaningful, and sustainable increases in activity that can facilitate weight loss.
The above list of “musts” may sound easy, but physicians may need to redesign care delivery to assist patients on their lifestyle transformation journey. The ROMEO study[10] demonstrated improved A1C outcomes, BMIs, and other endpoints through group as opposed to individual visits.
To be optimally effective, physicians also need to deliver lifestyle messages in a culturally sensitive manner. Project HEED[11] demonstrated that Spanish-speaking, low-income patients were able to lose (and maintain) significantly more weight than controls through peer-led lifestyle interventions. The Eat Well Live Well Nutrition Program also demonstrated satisfaction of participants in a culturally specific diabetes prevention program for African American women.[12]
Referrals to outside support groups may also be helpful. ADA standards recognize the limitations of office-based interventions alone and recommend patients with IGT or A1C of 5.7 to 6.4 be “referred to an ongoing support program for weight loss of 5-10%.” Physicians should have knowledge of such programs in their area for referral purposes. For example, United Health Group recently began partnering with Walgreens and the YMCA to allow at-risk members to access (at no cost) counseling and exercise sessions similar to the DPP.[13] Community-wide efforts for translating the DPP into practice are also being researched. The Healthy Living Partnership to Prevent Diabetes study (HELP PD) is studying the use of Community Health Workers (operating out of a Diabetes Care Center) who are employing weekly cognitive behavioral meetings to achieve >7% weight loss through increased physical activity and decreased caloric intake.[14]
In addition to continuing to encourage and support lifestyle changes that promote weight loss, close monitoring of this patient is also warranted given his increased risk of progression toward full-blown diabetes. Specifically, the physician should plan to monitor this patient’s A1C every 3-6 months.
See below for References and Disclosures.
References
1. 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 Feb 7;346(6):393-403.
2. WH, Hoerger TJ, Brandle M, et al. The cost-effectiveness of lifestyle modification or metformin in preventing type 2 diabetes in adults with impaired glucose tolerance. Ann Internal Medicine 2005 March;1142(5):323-332.
3. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001 May 3;344(18):1343-50.
4. Li G, Zhang P, Wang J, et al. The long-term effect of lifestyle interventions to prevent diabetes in the Chian Da Qing Diabetes Prevention Study: a 20-year follow-up study. Lancet 2008 May 24;371(9626):1783-1789.
5. Martinez-González MA, de la Fuente-Arrillaga C, Nunex-Cordoba JM, et al. Adherence to Mediterranean diet and risk of developing diabetes: prospective cohort study. BMJ 2008 June 14;336:1348-1351
6. Sofi F, Cesari F, Abbate R et al. Adherence to Mediterranean diet and health status: meta-analysis. BMJ 2008;337:a1344.
7. Utzschneider KM, Carr DB, Barsness SM, et al. Diet-induced weight loss is associated with an improvement in beta cell function in older men. J Clinl Endocrinol Metab 2004 June;89(6):2704-2710.
8. Diabetes Care. 2010 Mar 3. [Epub ahead of print]
9. Flemming D, von Linstow ME, Mikines KJ, et al. Physical training may enhance beta cell function in type 2 diabetes. Am J Physiol Endocrinol Metab 2004 November;287:E1024-E1031.
10. Trento M, Gamba S, Gentile L, et al. Rethink Organization to iMprove Education and Outcomes (ROMEO): a multicenter randomized trial of lifestyle intervention by group care to manage type 2 diabetes. Diabetes Care 2010 April;33:745-747.
11. Parikh P, Simon EP, Fei K, et al. Results of a pilot diabetes prevention intervention in East Harlem, New York City: Project Heed. Am J Public Health 2010 April;100(S1):S232-S239.
12. Williams JH, Auslander WF, de Groot M, et al. Cultural relevancy of a diabetes prevention nutrition program for African American women. Health Promotion Practice 2006;7(Mo1): 56-67.
13. Hobson, K. UnitedHealth to pay Walgreens, YMCA, for progress on diabetes. Wall Street Journal. April 13, 2010. Accessed April 15, 2010. http://blogs.wsj.com/health/2010/04/13/unitedhealth-to-pay-walgreens-ymca-for-progress-on-diabetes/?KEYWORDS=walgreens+united+health+group.
14. Katula JA, Vitolins MZ, Rosenberger EL, et al. Health Living Partnerships to Prevent Diabetes (HELP PD): design and methods. Contemporary Clinical Trials 2010 January;31(1):71-81.
Disclosure:
Doron Schneider has received honoraria for providing consultancy and acting as a speaker for Novo Nordisk.
Metformin
Irl B. Hirsch, MD
University of Washington School of Medicine
Seattle, WA
It is not surprising this patient’s HbA1c is rising due to the natural progression of beta cell failure in prediabetes and type 2 diabetes.[1] It is therefore unlikely that lifestyle modification alone will be effective in the long term. Many have wondered if using an agent that targets the basic defects of type 2 diabetes might retard progression to more advanced beta cell failure or even if simply reducing glucose-toxicity with an anti-glycemic drug might in and of itself slow the progression to diabetes. Metformin is a particularly attractive candidate along these lines as it is an older drug that is inexpensive, effective, and generally well tolerated. It has a modest benefit on diabetic dyslipidemia and is either weight neutral or results in modest weight loss. It may also improve several non-traditional risk factors such as endothelial activation and fibrinolysis, although the results for systemic inflammation are inconsistent.[2]
Metformin and Diabetes Prevention
Metformin was the first drug shown effective in preventing the transition from impaired glucose tolerance to diabetes, although in the Diabetes and Prevention Program (DPP) it was only about half as effective as intensive lifestyle changes. It needs to be emphasized that the DPP was a research study where one group of patients was randomized to intensive lifestyle changes with a goal of 7% weight loss and 150 minutes of daily exercise. In actuality, only 31% of metformin-treated and 58% of the intensive lifestyle change subjects were able to make that target. Metformin was also most effective in younger, more obese patients. However, because of these findings, metformin is the only drug recommended for patients with impaired glucose tolerance or impaired fasting glucose.[3] From this perspective, it could be argued the patient in this case study should have already been taking the drug.[4]
During the ten-year follow up of the DPP, subjects originally randomized to lifestyle modification were able to continue with this, while metformin subjects also remained on that drug. At the end of ten years, those randomized to lifestyle had gained some of their weight back but, more importantly, had a diabetes incidence rate reduced by 34% compared to placebo, while those using metformin had an 18% reduced incidence.[5] These findings not only speak to the progressive nature of the beta cell lesion but illustrate how neither approach is ideal long term. They also raise questions about the value of combining intense lifestyle changes with metformin therapy. Nevertheless, given the amount of time and effort provided to and by subjects in the lifestyle group, these results are likely the best one could hope for.
Given the DPP’s positive initial results, as well as the safety and affordability of metformin, the ADA recommends considering metformin in addition to lifestyle counseling in patients at very high risk for developing diabetes (i.e., patients with combined impaired fasting glucose and impaired glucose tolerance plus other risk factors such as HbA1c >6%, hypertension, low HDL cholesterol, elevated triglycerides, or family history of diabetes in a first-degree relative) and who are obese and under 60 years of age.[6] While the new DPP data do not suggest long-term success of metformin in preventing progression to diabetes, the use of this drug in addition to lifestyle seems to be the most obvious option for our patient. However, it should be noted that metformin, while recommended by the ADA for patients with similar histories and findings, is not formally approved by the US Food and Drug Administration for this use.
Metformin in Clinical Practice
Although the patient in our case does not yet meet criteria for diagnosis of type 2 diabetes, his physician might also consider that as monotherapy, metformin is as, or more, effective than other options in treating early type 2 diabetes.[7] In the often-referenced sub-study of obese patients with type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) randomized to metformin versus sulfonylureas and standard care, metformin improved a variety of endpoints, including any diabetes-related endpoint, diabetes death, and all-cause mortality. Although some argue this one study should not alone dictate all early therapy for type 2 diabetes, it is unique in its duration and robustness--one reason why the American Diabetes Association suggests metformin and lifestyle modification be “step 1” therapy for patients at diagnosis regardless of HbA1c level.[8]
As noted with the follow-up of the DPP, none of the therapies suggested for our sample patient would be ideal for long-term glycemic maintenance in diagnosed patients, due to progressive beta cell failure. For example, in the ADOPT Trial, five-year monotherapy failure was 25% with glyburide versus 15% for metformin and 10% for rosiglitazone as initial therapy for recently diagnosed type 2 diabetes.[9] In a large clinical practice setting, not part of a clinical trial, metformin monotherapy had even higher failure rates: 17% per year.[10] Importantly, however, the highest rates of metformin failure occurred when therapy was initiated later in the course of disease and in patients with higher HbA1c levels, again supporting the use of metformin early in the course of disease progression to preserve beta cell function. According to a Cochrane Review: “Sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, meglitinides, insulin, and diet fail to show more benefit for glycemic control, body weight, or lipids, than metformin.”[11]
Conclusion
For the treatment of our patient who is clearly losing the battle with progressive beta cell failure and rising blood glucose levels, there is sound evidence that metformin is an attractive option to delay the development of type 2 diabetes further. Unfortunately, none of our therapies has been found ideal for long-term use in studies of large patient populations, which makes “combination therapy” even more desirable assuming such therapies are both effective and safe. The first combination that should be used is continued lifestyle modification with metformin, an approach recommended by the ADA even though there are no studies using these two strategies in combination. Given the public health burden of type 2 diabetes, combinations of pharmacologic therapies in high-risk patients like the one in this case will hopefully be considered in the future as well.
See below for References and Disclosures.
Comments
Posted 10/6/11 by abelardo
de acuerdo a algunos estudio que sugieren un defecto incretina con aumento de glucacon en fases temprana, que opinan de combinacion farmacologica temprana dirigida a la patofisiologia Metformina +IDPP4_ podria ser mas efectivo en retrasar la transicion de prediabetes a diabetes en paciente de alto riesgo
Posted 10/6/11 by abelardo
de acuerdo a algunos estudio que sugieren un defecto incretina con aumento de glucacon en fases temprana, que opinan de combinacion farmacologica temprana dirigida a la patofisiologia Metformina +IDPP4_ podria ser mas efectivo en retrasar la transicion de prediabetes a diabetes en paciente de alto riesgo
Posted 11/4/10 by M Osman MD
I agree metformin should be added for such patients. The only clinical trial evidence for combining life style and metformin was the Indian diabetes prevention program published in diabetologia (please see the IDF website diabetes prevention trials section)
Posted 10/15/10 by Irl Hirsch
It's difficult to argue with anything you say-I'd be curious how many people who COULD benefit from metformin (and are receiving medical care) are not. Part of the problem is that the drug isn't really promoted anymore since it is generic, but even if it wasn't, use of metformin for pre-diabetes is not on the US FDA "label". It is a bit of a circular discussion since a pharmaceutical company has to do the trial (as done in the DPP) and then apply after the study to get it on label. I suspect two studies would be required as that is what is required for most items to get approval by FDA, but this is all academic at this point. What I think is needed is more education to let both patients and clinicians appreciate that metformin can be an important addition for patients with pre-diabetes.
Posted 8/26/10 by Dr. Gauranga C. Dhar.
Till today there is no specific guideline to prevent development of T2DM from pre-diabetes by metformin but according to pharmacology, I think this may be a unique drug for such purpose. Prediabetes—either impaired fasting glucose, impaired glucose tolerance, or both—can result in overt diabetes within a few years. The key pathophysiologic factor for prediabetes and the subsequent onset of type 2 diabetes is insulin resistance. In normal subjects, insulin stimulates glucose uptake by skeletal muscle cells, adipose tissue, and hepatocytes. In insulin resistance, these tissues can not uptake glucose molecules through translocation of GLUT4 and because of compensatory mechanisms more and more insulin is secreted by β-cells, causing hyperinsulinemia. As a result of continuous pressure, β-cells ultimately fail to produce an adequate insulin response to glucose, leading to type 2 diabetes.
Lifestyle modifications, such as diet and physical exercise, of course have a great value to the reduction of insulin resistance and the prevention of new onset type 2 diabetes. As a drug therapy, metformin, by reducing hepatic glucose production and increasing insulin sensitivity in peripheral tissue, can substantially reduce the process of transforming prediabetes to type 2 diabetes.
I think all patients in the stage of pre-diabetes should start metformin unless contraindicated which will not only prevent development of T2DM but can offer favorable effects on other metabolic abnormalities and of course cardio-protection through its beneficial effects on atherosclerosis and macro-vascular complications in patients with pre-diabetes and also overt diabetes who already suffer from endothelial dysfunction possibly a decade ago from the development of dysglycemia.
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References
1. United Kingdom prospective diabetes study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulfonylurea, insulin, or metformin in patients with newly diagnosed non-insulin-dependent diabetes followed for three years. BMJ 1995 Jan 14;310(6972):83-88.
2. Caballero AE, Delgado A, Aguilar-Salinas CA, et al. The differential effects of metformin on markers of endothelial activation and inflammation in subjects with impaired glucose tolerance: a placebo-controlled, randomized clinical trial. J Clin Endocrinol Metab 2004;89:3943-3948
3. Nathan DM, Davidson MB, DeFronzo RA, et al: Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007;30:753-759.
4. Knowler WC, Barrett-Conner 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.
5. Knowler WC, Fowler SE, Hamman RF. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet 2009 Dec 19;374(9702):1677-1686.
6. ADA Standards of Medical Care in Diabetes. Diabetes Care 2010;33(Suppl. 1):S11-61.
7. Inzucchi SE. Oral antihyperglycemic agents for type 2 diabetes: scientific review. JAMA 2002;287:360-372, 2002.
8. Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement of the American Diabetes Association and European Association for the Study of Diabetes. Diabetes Care 2009;32:193-203.
9. Kahn SE, Haffner SM, Heise SA, et al. Glycemic durability of rosiglitazone, metformin, and glyburide monotherapy. N Engl J Med 2006 355:2427-43.
10. Brown JB, Conner C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care 2010;33:501-506.
11. Saenz A, Fernandez-Esteban I, Mataix , et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews. Issue 3. Art. No.: CD002966. DOI: 10.1002/14651858.CD002966.pub3
Disclosure:
Irl Hirsch is the principal investigator for a clinical trial sponsored by Novo Nordisk.
Thiazolidinedione (TZD)
Jack L. Leahy, MD
University of Vermont College of Medicine
Burlington, VT
Our patient has a family history of type 2 diabetes and metabolic syndrome along with worsening obesity despite attempting lifestyle modification. He also has a documented rise of his A1c plus a fasting glucose value, both of which signal pre-diabetes. Finally, he’s concerned and wants to do whatever possible to prevent full-blown diabetes.
While lifestyle modification or metformin are the most common recommendations for a patient like this, my vote is to also consider a thiazolidinedione (TZD) based on proven efficacy, although side effects and/or cost get in the way of this being recommended very often for patients with pre-diabetes.
Proven Efficacy in Preventing Diabetes
Several clinical trials have used TZD therapy in patients with noteworthy pre-diabetes. The TRIPOD[1]and PIPOD[2] studies from Buchanan and coworkers tested a TZD (trogliazone in TRIPOD, pioglitazone in PIPOD) in Hispanic women in Los Angeles who previously had gestational diabetes. The prominence of these studies was due to this population’s extreme risk of moving onto full-blown type diabetes (nearly 50% within five years after delivery), as well as the dramatic findings: 55% reduction in diabetes onset during the 30 months of the TRIPOD study, and continuation of that protection when patients were switched to pioglitazone after troglitazone was taken off the market because of hepatotoxicity. On the other hand, these findings have been questioned due to their relatively few subjects and select patient population involved. The next study--the DREAM study[3]--lessened those concerns considerably. It was a large (n=5269) worldwide study of subjects with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both, who received 8 mg of rosiglitazone daily or placebo for a median of three years. Rosiglitazone lowered the diabetes incidence from 25% in the placebo group to 10.6%, i.e., nearly a 60% reduction.
Collectively, these results showed a 55-60% reduction in diabetes incidence. That number is important as it equals the 58% reduction with intensive lifestyle intervention in the US-based Diabetes Prevention Program (DPP)[4] and the Finnish Diabetes Prevention Study,[5] that are used to support the general belief that lifestyle intervention has given the best results in type 2 diabetes prevention studies. Even more informative is to closely scrutinize the DPP study. It tested three interventions in more than 3800 subjects with IGT--intensive lifestyle program that included dietary and exercise behavioral support, metformin 850 mg twice daily, or troglitazone 400 mg daily--and compared them to a control arm of standard healthy lifestyle recommendations, with percent conversion to diabetes over the average 2.8 years of the study as the endpoint. However, because the troglitazone arm was stopped early because of a case of fatal liver failure that contributed to that drug’s removal from the market, these subjects were not included in the high profile paper published in the New England Journal of Medicine.4 Even so, those results did appear in little known second paper that compared results from all four treatment arms over the average nine months exposure to troglitazone.[6] Diabetes incidence rate was 3.0 cases per 100 years for troglitazone versus 12.0 for control, in contrast to 6.7 for metformin, and 5.1 in the intensive lifestyle group. In other words, the TZD was the most effective preventive approach, at least initially.
So, score one for TZDs in terms of efficacy, which seems at least as good as the commonly used interventions, if not better.
Mechanism of Action Supporting Beta Cell Protection
A second argument for TZD therapy is a proposed mechanism of action that seems tailor-made for pre-diabetes patients. Cross-sectional and prospective studies of many populations have shown that the progression of normal glucose tolerance to pre-diabetes to diabetes stems from a progressive worsening of beta cell function. As such, the ultimate goal of a prevention therapy should be stabilizing beta cell function. Consistent with this, Buchanan showed that at the start of the TRIPOD study1 that his subjects were insulin resistant but also had a high level of insulin secretion preventing hyperglycemia, a phenomenon known as beta cell compensation. Diabetes resulted when insulin secretion fell relative to the degree of insulin resistance, so-called beta cell failure. Furthermore, troglitazone maintained the original relationship between insulin secretion and sensitivity, thus preventing diabetes through substantial improvements in both insulin sensitivity and insulin secretion. Within this pair of observations, Buchanan’s team focused on the fall in insulin secretion and concluded that troglitazone had induced a beta cell rest effect. Importantly, with this conclusion and additional studies by these and other authors, focus for TZD’s effect in pre-diabetes has shifted from insulin sensitization per se to beta cell preservation. In theory, lifestyle intervention or metformin might act similarly, although neither of these other approaches is as powerful as TZDs in terms of insulin sensitization.
Finally, TZDs act on the PPAR-gamma signaling pathway in tissues, which a growing literature suggests might play a role in regulating the mass of islet beta cells.[7] However, it’s too early to know what relevance this might have to the clinical use of TZDs in pre-diabetes.
Score two for TZDs in terms of linking their use to beta cell protection mechanisms.
The Downside
Why haven’t TZDs been advocated for usage in prediabetes--at least on the list of proven agents, if not at the top? The simple answer is that every positive study has been balanced by an editorial or other opinion that looks not only at diabetes prevention, but also at other results such as more weight gain, congestive heart failure, and cost and concludes on balance that other therapies, while perhaps not as effective, are safer and cheaper.
Returning to our patient, he has no cardiac history and is generally healthy, and he’s looking for the best diabetes protection he can get. Based on the above, one can make a strong argument that TZDs fit that bill at least as well, if not better than, lifestyle modification alone or with metformin.
See below for References and Disclosures.
Comments
Posted 4/3/13 by Graham A Morgan
The information on this site really helps me to complete my assignment..
Very informative and concise..I will continue to use this site for my assignments and other major projects..
Kind Regards
Graham Anassah Morgan
Pacific Adventist University, Port Moresby
Papua New Guinea
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References
1. 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 Sept;51(9):2796-2803.
2. Xiang AH, Peters RK, Kjos SL, et al. Effect of pioglitazone on pancreatic beta cell function and risk in Hispanic women with prior gestational diabetes. Diabetes 2006 Feb;55(2):517-522.
3. Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Lancet 2006 Sept 23;368(9541):1096-1105.
4. 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 Feb 7;346(6):393-403.
5. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001 May 3;344(18):1343-1350.
6. Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the diabetes prevention program. Diabetes 2005 April, 54(4):1150-1156.
7. Leahy JL. Thiazolidinediones in prediabetes and early type 2 diabetes: what can be learned about that disease’s pathogenesis. Curr Diab Rep 2009 June;9(3):215-220.
Disclosure:
Jack Leahy has served as an advisor or consultant within the last 12 months for Novo Nordisk, Sanofi Aventis, Merck, and Daiichi Sankyo.
Cast a vote to see the results.
Option #2
Posted 10/6/11 by abelardo
de acuerdo a algunos estudio que sugieren un defecto incretina con aumento de glucacon en fases temprana, que opinan de combinacion farmacologica temprana dirigida a la patofisiologia Metformina +IDPP4_ podria ser mas efectivo en retrasar la transicion de prediabetes a diabetes en paciente de alto riesgo
Option #2
Posted 10/6/11 by abelardo
de acuerdo a algunos estudio que sugieren un defecto incretina con aumento de glucacon en fases temprana, que opinan de combinacion farmacologica temprana dirigida a la patofisiologia Metformina +IDPP4_ podria ser mas efectivo en retrasar la transicion de prediabetes a diabetes en paciente de alto riesgo
Option #2
Posted 11/4/10 by M Osman MD
I agree metformin should be added for such patients. The only clinical trial evidence for combining life style and metformin was the Indian diabetes prevention program published in diabetologia (please see the IDF website diabetes prevention trials section)
Option #2
Posted 10/15/10 by Irl Hirsch
It's difficult to argue with anything you say-I'd be curious how many people who COULD benefit from metformin (and are receiving medical care) are not. Part of the problem is that the drug isn't really promoted anymore since it is generic, but even if it wasn't, use of metformin for pre-diabetes is not on the US FDA "label". It is a bit of a circular discussion since a pharmaceutical company has to do the trial (as done in the DPP) and then apply after the study to get it on label. I suspect two studies would be required as that is what is required for most items to get approval by FDA, but this is all academic at this point. What I think is needed is more education to let both patients and clinicians appreciate that metformin can be an important addition for patients with pre-diabetes.
Option #1
Posted 10/11/10 by Steve Freed
For this patient who is very close to the diagnosis of diabetes, we need to be aggressive in his treatment. This could be accomplished with aggresive life style changes. But, just telling the patient to change, usually will not work.
The first treatment should be EDUCATION, without the correct knowledge on why they need to change and what they can personally do about it, they will fail.
They need to understand diabetes and how it progresses and what the final outcomes can be with lifestyle changes.
Just having your patients understand how carbohydrates play a role and how to count carbohydrates and have them responsible for reporting their carbohydrate intake to their physican can have a major effect.
Having them get a simple tool like a pedometer and have them report to their doctor their daily steps and setting a goal for them can also be just as effective as any medication.
The responsibility of the physician is not to educate the patient, but it is their responsibility to get their patients educated.
Steve Freed, R.Ph.,CDE, Publisher
www.diabetesincontrol.com
Option #1
Posted 10/23/10 by Doron Schneider, MD
I agree with the need to educate. In addition to a general education to count calories and carbohydrates as you suggest there are many additional studies that demonstrate glycemic benefit from targeted dietary approaches. Directing patients to learn more about Mediterranean diets, what foods contain whole grains, understanding the benefits of simple substitutions – such as brown rice instead of white and teaching about the benefits of supplementation with readily available items such as psyllium should all be within reach of primary care doctors. We need to empower patients to make the right decisions… It is certainly about education!
Option #3
Posted 4/3/13 by Graham A Morgan
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Kind Regards
Graham Anassah Morgan
Pacific Adventist University, Port Moresby
Papua New Guinea
Option #2
Posted 8/26/10 by Dr. Gauranga C. Dhar.
Till today there is no specific guideline to prevent development of T2DM from pre-diabetes by metformin but according to pharmacology, I think this may be a unique drug for such purpose. Prediabetes—either impaired fasting glucose, impaired glucose tolerance, or both—can result in overt diabetes within a few years. The key pathophysiologic factor for prediabetes and the subsequent onset of type 2 diabetes is insulin resistance. In normal subjects, insulin stimulates glucose uptake by skeletal muscle cells, adipose tissue, and hepatocytes. In insulin resistance, these tissues can not uptake glucose molecules through translocation of GLUT4 and because of compensatory mechanisms more and more insulin is secreted by β-cells, causing hyperinsulinemia. As a result of continuous pressure, β-cells ultimately fail to produce an adequate insulin response to glucose, leading to type 2 diabetes.
Lifestyle modifications, such as diet and physical exercise, of course have a great value to the reduction of insulin resistance and the prevention of new onset type 2 diabetes. As a drug therapy, metformin, by reducing hepatic glucose production and increasing insulin sensitivity in peripheral tissue, can substantially reduce the process of transforming prediabetes to type 2 diabetes.
I think all patients in the stage of pre-diabetes should start metformin unless contraindicated which will not only prevent development of T2DM but can offer favorable effects on other metabolic abnormalities and of course cardio-protection through its beneficial effects on atherosclerosis and macro-vascular complications in patients with pre-diabetes and also overt diabetes who already suffer from endothelial dysfunction possibly a decade ago from the development of dysglycemia.
Option #1
Posted 7/27/10 by Stephen Brunton
Of course lifestyle modification has an important role in this patient as it has with all patients with the metabolic syndrome but unfortunately if may not be enough. This is not an either/or situation but a lifestyle plus....either metformin, a TZD or maybe an incretin...With the current pandemic of obesity (and inactivity) a realization of the consequences of this situation will hopefully result in an appropriate medical and social response.
Option #1
Posted 9/13/10 by Doron Schneider
This patient may not need medications such as metformin (as evidenced by the DPP) if they had access to well planned and coordinated lifestyle modification programs such as outlined in the case response. Most Primary Care offices are not designed to be able to provide this level of service. It is thus critical that PCPs understand what similar options exist in their communities for these patients and refer! Simply telling people to exercise more and eat less is not sufficient. Thanks for your comment...
Comments
For this patient who is very close to the diagnosis of diabetes, we need to be aggressive in his treatment. This could be accomplished with aggresive life style changes. But, just telling the patient to change, usually will not work.
The first treatment should be EDUCATION, without the correct knowledge on why they need to change and what they can personally do about it, they will fail.
They need to understand diabetes and how it progresses and what the final outcomes can be with lifestyle changes.
Just having your patients understand how carbohydrates play a role and how to count carbohydrates and have them responsible for reporting their carbohydrate intake to their physican can have a major effect.
Having them get a simple tool like a pedometer and have them report to their doctor their daily steps and setting a goal for them can also be just as effective as any medication.
The responsibility of the physician is not to educate the patient, but it is their responsibility to get their patients educated.
Steve Freed, R.Ph.,CDE, Publisher
www.diabetesincontrol.com
I agree with the need to educate. In addition to a general education to count calories and carbohydrates as you suggest there are many additional studies that demonstrate glycemic benefit from targeted dietary approaches. Directing patients to learn more about Mediterranean diets, what foods contain whole grains, understanding the benefits of simple substitutions – such as brown rice instead of white and teaching about the benefits of supplementation with readily available items such as psyllium should all be within reach of primary care doctors. We need to empower patients to make the right decisions… It is certainly about education!
Of course lifestyle modification has an important role in this patient as it has with all patients with the metabolic syndrome but unfortunately if may not be enough. This is not an either/or situation but a lifestyle plus....either metformin, a TZD or maybe an incretin...With the current pandemic of obesity (and inactivity) a realization of the consequences of this situation will hopefully result in an appropriate medical and social response.
This patient may not need medications such as metformin (as evidenced by the DPP) if they had access to well planned and coordinated lifestyle modification programs such as outlined in the case response. Most Primary Care offices are not designed to be able to provide this level of service. It is thus critical that PCPs understand what similar options exist in their communities for these patients and refer! Simply telling people to exercise more and eat less is not sufficient. Thanks for your comment...
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