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Glycemic control for macrovascular disease in type II diabetes: Evidence and insights from recent trials
j o u r n a l o f i n d i a n c o l l e g e o f c a r d i o l o g y 5 ( 2 0 1 5 ) S 8 3 eS 9 4
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/jicc
Glycemic control for macrovascular disease in type II diabetes: Evidence and insights from recent trials Sanjay Rajagopalan Division of Cardiovascular Medicine, University of Maryland, Baltimore, MD, USA
article info Article history: Received 19 January 2015 Accepted 11 February 2015
1.
Diabetes and survival
This data is from 97 prospective studies taken from a population cohort study called the “Emergent Risk Factors Collaboration” (NEJM, 2011). This data clearly shows that the life expectancy is reduced by 6e7 years in a patient who is diagnosed with diabetes since middle age, irrespective of the gender. Most of the reduction in life years in type 2 diabetics is driven by approximately 56% contribution by vascular mortality. There is also a big contribution by non-cancer, nonvascular death but the predominant cause in mortality in the type 2 diabetic is cardiovascular complications (Fig. 1). There is underutilization of therapies in India, which is clearly the epicenter of type 2 diabetes. There will be significant advances and there have been implementation of guidelines.
2.
Event rates in type II diabetes mellitus
This research by Gregg and coworkers (Gregg et al, NEJM, 2014) observed the age-standardized rates of diabetes rate of complications in North American adults. This was taken from a variety of different sources. Some of the complications in type 2 diabetics are acute myocardial infarction, stroke, amputation, and end-stage renal disease. The reductions in these complications in type 2 diabetes over a 20-year period, from 1990 to 2010 are Nothing short of remarkable. 67% reduction in
myocardial infarction has been observed (Fig. 2). There could be a number of reasons for this: (i) individual behaviors, (ii) diet, (iii) activity, (iv) use of pharmacologic therapies, (v) implementation of guidelines, and (vi) systems based approaches for the management of type 2 diabetes. Hopefully, this will also happen in India in the years to come with appropriate implementation of multifactorial strategies. Fig. 3 depicts the occurrence of cardiovascular event rates as observed in various trials of diabetes. UKPDS is a trial that was designed in the 1970s or 1980s, and a more contemporary trial like ORIGIN. Both these studies were quite similar, since both of them recruited new-onset type 2 diabetics, people with impaired fasting glucose and glucose intolerance. A significant reduction in annual event rates in these 2 trials can be picked up immediately. A similar trend is also seen in contemporary clinical trials for revascularization in type 2 diabetes such as FREEDOM which is a contemporary clinical trial, compared with BARI 2D (Fig. 4). The cause of reductions in cardiovascular events in the type 2 diabetics in the western hemisphere and the change in baseline risk factors are attributable to the usage of pharmacologic strategies which are very effective. That is the message that needs to be emphasized. The UKPDS trial that randomized new-onset type 2 diabetics, roughly within 3 years of the diagnosis to an intensive glucose lowering strategy, either using sulfonylureas or insulin or comparatively less intensive strategy. The endpoint in UKPDS was a composite endpoint of every conceivable complication of type 2 diabetic. This actually turned out to be a very useful way to look at this because measurement of all complications in type 2 diabetics is possible. The risk for type 2 diabetics is more than merely cardiovascular risk; it includes microvascular complications such as nephropathy, and retinopathy. It also includes myocardial infarction, stroke and amputation for peripheral vascular disease. Any diabetes-related endpoint was reduced with the usage of intensive insulin-based
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jicc.2015.03.006 1561-8811/Copyright © 2015, Indian College of Cardiology. All rights reserved.
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Fig. 1 e Survival data from 820,900 individuals in 97 prospective studies. Source: Seshasai SR, et al. N Engl J Med. 2011; 364(9):829e841
treatments. The majority of risk reduction with intensive treatment of glucose in UKPDS was driven by microvascular complications. The confidence intervals for myocardial infarction actually crossed unity, suggesting that it was not statistically insignificant (Fig. 5). At the end of 2000, after the results of UKPDS were announced, the relationship between microvascular disease and HbA1c was established. The risk keeps going down with
reducing levels of HbA1c, all the way down to less than 6 (Fig. 6). According to the guideline committee there was no robust evidence for target of HbA1c less than 7, but the continuing relationship between HbA1c reduction in the UKPDS shows that risk reduction continues to HbA1c levels of less than 6%. Maybe an extension of this recommendation is needed, and starting recommendation to target HbA1c levels of less than 7
Fig. 2 e Trends in age-standardized rates of diabetes-related complications in U.S adults. Source: Gregg EW et al. NEJM. April 17, 2014; 370; 1514e1523
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Fig. 3 e Annual event rate due to coronary heart disease and MI observed in various diabetes trials.
Fig. 4 e Comparison of the BARI 2D and the SYNTAX trials, in terms of CV events.
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is probably good. This is the basis of recommendation dating back to 2000 and various guideline societies have continued to suggest till date, lowering HbA1c to less than 7 might be beneficial from a microvascular perspective. The curve is much more flat for myocardial infarction as shown in Fig. 6. UKPDS clearly suggested that for every 1% reduction in HbA1c, there was a 21% reduction in diabetes rated deaths, and 37% reduction in microvascular endpoints. Incremental lowering in HbA1c was interpreted as being beneficial for patients. “As low as you can get” was probably the view of the world back in the early 2000s. But it was quickly realized that HbA1c just like blood pressure has limitations. Lower levels of HbA1c not surprisingly were associated with a higher risk of hypoglycemia (Fig. 7). There is a limit to which the HbA1c can be lowered, and the question is what is that limit and does that vary for a particular patient. Although the microvascular complications go down in about 4 years' time, but regarding macrovascular disease, there was no robust evidence. Appropriately powered clinical trials such as ACCORD, ADVANCE, or VA-DT were designed, keeping this factor in mind. Fig. 7.1 shows the baseline HbA1c for these 3 trials. ADVANCE aimed at bringing the HbA1c to less than 6.5%, and ACCORD aimed for lower HbA1c of 7.9% and 6% (depending upon the group). VADT set a more conservative goal HbA1c of 7%. These are relatively large studies but the median duration follow-up was approximately 4e6 years, 5.6 years for VA-DT (Fig. 7.2).
Fig. 5 e Blood glucose levels and vascular risk in diabetes e Best Evidence. (Diabetes Related End-Points: Sudden death, death from hyperglycemia or hypoglycemia, fatal or non-fatal MI, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction). Source: UK Prospective Diabetes Study Group. Lancet. 1998; 352(9131):837e853
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Fig. 6 e Blood glucose and vascular risk in diabetes best evidence: 2000. Source: Stratton IM, et al. BMJ. 2000; 321(7258):405e412
There were higher rates in mortality in the intensive treatment arm in the ACCORD trial, and it was stopped prematurely at 3.6 years. ADVANCE was different because the endpoint was a combination of microvascular and macrovascular endpoints, just like UKPDS, and it was a positive study. There was a reduction in the primary endpoint in ADVANCE. In VA-DT, there was no change in a very similar endpoint to ACCORD (death plus myocardial infarction). All of these trials showed an increase in hypoglycemia with intensive insulin regimens. Fig. 8 provides the summary of all of this information. Microvascular disease is exquisitely sensitive to glycemia control and if a drug lowers HbA1c, it might lower microvascular complications. Cardiovascular risk reduction seems to be evident, at least in the follow-up studies when the patients are followed up for long term beyond the trial duration. Keeping in mind that all these trials are 5 years and following up the patients for a much longer duration like 10 years, there might be differences in cardiovascular disease. This is certainly the case with a long-term 10 year follow-up of UKPDS and the long-term follow-up of DCCT/EDIC (trial in type 1 diabetes). Both of these trials show that if patients are followed long enough, a benefit in cardiovascular disease will be seen. The long-term follow-up was in the positive 33% reduction in the metformin arm in UKPDS with the follow-up.
3.
Hypoglycemia as a risk marker
Hypoglycemia was a problem and all of these trials consistently show that induction of major hypoglycemia in a patient with type 2 diabetes is a risk factor for future cardiovascular events (Figs. 9 and 10). If a patient is prone to hypoglycemia, avoidance of aggressive glycemia lowering for obvious reasons and from a cardiovascular perspective is advisable. There is approximately a 2-1/2 fold increase in hazard ratio for cardiovascular events if hypoglycemic events are frequent. This is also seen in the post-hoc analysis, which shows that if hypoglycemia develops even within a 3-month period or a 6month period, there was a very strong association with
predisposition to macrovascular events and death from any cause. They point very robust signals by 3-1/2 fold increase or death from cardiovascular causes. Hypoglycemia, therefore, is an adverse risk prognosticator for cardiovascular reasons. There is a variety of different mechanisms that have been postulated, namely, sympathetic imbalance, vagal imbalance, etc.
4. Legacy and vintage effects in diabetes mellitus The other important concept that needs to be understood is the concept of legacy. This is important in the Indian context because there were several questions pertaining to statin therapy in type 2 diabetics and do we stop glycemia lowering after a certain duration and do these effects persist? For instance, consider a patient who participated in a clinical trial, and treated for 2- to 3-year period or a 4-year period and eventually, the trial patients went back in the usual behavior where they were not rigorously controlled anymore. The beneficial effects of this treatment might persist for as long as 10 years after stopping the therapy. This phenomenon of lasting beneficial effects of interventions done early in the course of disease is what the endocrinologists refer to as the “legacy effect”. There is a legacy of treatment effect that you divine many years after treatment which is certainly seen in type 2 diabetics. That is not to say that treatment should stop. It just goes to show that the treatment effects over time can persist; and really underscores the importance of treatment early on so that the treatment benefits coming on board several years down the line after starting treatment. The other concept was out of vintage which refers the duration of type 2 diabetes, and to what extent treatment has affected the course of the disease. This is a long-term follow-up of UKPDS. During the shortterm, there was no signal for macrovascular events, but on long term follow-up for 10 years, the HbA1c curves converge. In other words, they were no different between intensive
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Fig. 7 e Benefit and risks of blood glucose control coexist: Evidence from UKPDS. The risks of diabetes complications significantly reduced for every 1% reduction of HbA1c. 1: Glycemia trials in perspective. 2: Glycemic targets set by various trials.
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Fig. 8 e Impact of intensive therapy for diabetes: Legacy and vintage effects for CV events.
glycemia lowering group and the usual conventional care group. Despite the HbA1c becoming convergent, there was a benefit in terms of mortality; 13% reduction in mortality at 10 years, at the end of participating in UKPDS. There is also a reduction in myocardial infarction (Fig. 11). In the patients that participated in long duration trials like VA-DT and ACCORD, it might not be possible to see changes in
myocardial infarction within a 5-year duration. A longer duration would be needed. In some cases, the disease has progressed so far, that a reduction in macrovascular events might not be possible. This has implications for design of clinical trials. Historically, clinical trialists were of the opinion to include the sickest patients in clinical trials since the sample size can be lower and the studies can be sufficiently powered. These patients are going to have events but these are precisely the type of patients where a reduction in cardiovascular events may not be seen because of the problem of “vintage” effect (Fig. 12). Fig. 13 shows the UKPDS patient population with recentonset type 2 diabetes, in whom lowering of glucose was done aggressively. They didn't have bad plaque memory or much of atherosclerosis since they are recent-onset type 2 diabetics. Contrast that with somebody participating in ACCORD, ADVANCE, and VA-DT; they have a lot of biologic memory. In other words, they have a lot of plaque with complications. In such patients, even if the HbA1c is driven down aggressively, a significant reduction in cardiovascular events may not be seen.
Fig. 9 e Hypoglycemia in the landmark trials. Source: Turnbull FM, et al. Diabetologia. 2009;52(11):2288e2298
Fig. 10 e Incident vascular outcomes and death among patients who had severe hypoglycemia in ADVANCE. Source: Zoungas N,et al. Engl J Med. 2010 Oct 7; 363(15):1410e8
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Fig. 11 e 10 year follow-up of UKPDS. Source: Holman R et al. N Engl J Med 2008; 359:1577e89
5.
Multifactorial intervention
Interventions of lifestyle choices, physical activity, will have huge benefits in terms of changing incidence, very dramatically, and very soon. Small amounts of weight loss makes a huge difference in insulin sensitivity as has been demonstrated repeatedly in multiple studies. It is no surprise that
lifestyle intervention in the short term is highly effective in reducing propensity to development of type 2 diabetes. This has been an international experience, irrespective of the country, the Da Qing study in China (Pan et al, Diab Care, 1997), the Indian Diabetes Prevention Program (Ramachandran A, diabetologia, 2009). Many of these trials also show long-term reductions and in follow-up. For instance, a 20-year follow-up of the Chinese diabetes study shows a 43% reduction in type
Fig. 12 e Effect of duration of diabetes (“vintage”) and other pre-specified sub-groups on major cardiovascular events. Source: Turnbull FM, et al. Diabetologia. 2009; 52(11):2288e2298
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Fig. 13 e Heart disease prevention with improved glycemic control: Start early and continue long-term.
Fig. 14 e Steno-2: Effects of multifactorial intervention on CV outcomes. Source: Gaede P, et al. N Engl J Med. 2008; 358(6):580e591
2 diabetes which is pretty remarkable. In a country like India, these are extremely cost effective interventions, and there is no question that lifestyle choices or lifestyle intervention trials are at the core of the treatment of type 2 diabetes. Indeed,
Weight loss of greater than 7% in exercise is fundamental in the treatment approach (Gregg et al, 2012, JAMA). The Steno-2 is probably one of the smallest studies that showed such remarkable benefits. The one remarkable thing
Fig. 15 e Effect of early intensive therapy on outcomes detected by screening. Source: Griffin SJ, et al. Lancet. 2011;378(9786):156e167
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Fig. 16 e Summary of pharmacological incretin action on different target tissues.
that Steno-2 did, that many of the other more contemporary multifactorial intervention trials did not do was smoking cessation. It is a very important part of intervention, but smoking, including secondhand smoke, continues to be a major risk factor. This is intervention is particularly important in type 2 diabetics (Fig. 14).
This type of intervention when extrapolated to contemporary European sites, results are much less effective compared to Steno-2 (Fig. 15). This doesn't argue against risk factor modification and aggressive control, but the fact that it takes a lot to reduce risk in type 2 diabetics. If it is to be done along with other interventions like smoking cessation in a
Fig. 17 e Macrovascular outcome trials.
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Fig. 18 e SAVOR-TIMI primary outcome measure. Source: Scirica BM, et al.N Engl J Med. 2013 Oct 3;369(14):1317e6 and AHA Scientific Session, 2013
Fig. 19 e 1: SAVOR-TIMI: Individual Endpoints of Secondary Composite End-Point: Expanded MACE. 2: SAVOR-TIMI: Risk of hospitalization for HF according to baseline NT-proBNP. Source: Scirica BM, et al.N Engl J Med. 2013 Oct 3;369(14):1317e6 and AHA Scientific Session, 2013
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patient population with high prevalence of risk factors such as smoking, a very remarkable effect can be obtained.
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in a lot of debate about whether this is a class effect or the DPP-4 inhibitors cause heart failure, which this remains to be determined. Certainly, the signals have been raised with Saxagliptin, not with Alogliptin.
6. how you lower glucose does make a difference 7. This takes us back to the first question. Not all drugs are created equal. There could be a drug that is remarkably effective in lowering HbA1c but it might have an adverse effect on mortality. The example of this would be a recent drug which is a PPARalpha, PPAR-gamma activator. The idea is if we could combine the pioglitazone with a fibrate like fenofibrate and come up with a combination molecule, we could get the benefits of PPARalpha agonism and also PPAR-gamma agonism. As opposed to pioglitazone, which shows the benefit, something like aleglitazar (combined PPAR-alpha and gamma agonist) is very effective in reducing HbA1c but it actually increases mortality. It reduces HbA1c, triglycerides, and it increases HDL cholesterol, a modest effect in increasing LDL cholesterol, but it increased heart failure, fractures, GI complication rate. The ORIGIN trial compared insulin glargine versus standard care. The primary endpoint was a hazard ratio of 1.02 for mortality in cardiovascular events. Soon after treating 6e7 years, normalizing plasma glucose with insulin glargine, reducing HbA1c, reducing fasting glucose does not seem to have an effect on cardiovascular mortality. In fact, this is associated with more weight gain and hypoglycemia. The newest drugs in the market are the DPP-4 inhibitors and incretin-based therapies, and all clinicians are waiting with bated breath to find out more about GLP-1agonist. They lower HbA1c on an average by about 0.8e1%, they lower weight. They also seem to have some favorable effects in blood pressure, but the question is they lower cardiovascular mortality? As seen in Fig. 16, the effects of incretin-base therapies seem to be all the right things. The question is whether these changes in surrogate measures including glycemia control translate into reduction in cardiovascular events and Fig. 17 summarizes all of the outcome trials. These include the EXAMINE study (primary safety study) that included patients with acute coronary syndrome, randomized them to Alogliptin versus placebo and evaluated the safety. There was no difference in terms of cardiovascular death, nonfatal myocardial infarction, and stroke in the Alogliptin, as compared to placebo. There was no difference between the 2 groups and the treatment was safe. But this did not meet the superiority, a secondary hypothesis. There was also a recent concern about heart failure with these patients. A post-hoc pre-specified analysis of composite endpoint inclusive of hospitalized heart failure in the Alogliptin versus placebo was done, and the P-values are non-significant. There was a little bit of trend towards increases in heart failure cases but this was not borne out in subsequent analyses. Another trial was the SAVOR-TIMI trial, which compared Saxagliptin with placebo. The primary endpoint in this trial was a superiority analysis, which this trial did not meet (Fig. 18). The interesting thing was in this study; hospitalization for heart failure which is again a pre-specified secondary endpoint was higher by approximately 27% in the Saxagliptin arm compared to placebo (Fig. 19.1 and 19.2). This has resulted
Conclusion
Lowering glucose reduces microvascular complications within a 5-year time window, macrovascular events might take a longer duration. Drugs used to accomplish glycemic control may have independent effects, which is why the regulatory authorities have mandated cardiovascular safety trials. Just because the drug reduces HbA1c does not necessarily make it effective to lower cardiovascular complications. This must be done for any new drug undergoing evaluation. DPP-4 inhibition appears to be cardioprotective from a preclinical perspective.
Conflicts of interest The author has none to declare.
Acknowledgement I would like to acknowledge efforts of Dr. Rishi Jain and Dr. Medhinee Kulkarni for their assistance in drafting this manuscript.
further reading
1. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358:2545e2559. http://dx.doi.org/10.1056/ NEJMoa0802743. Epub 2008 Jun 6. PubMed PMID: 18539917. 2. Duckworth W, Abraira C, Moritz T, et al, VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360:129e139. http:// dx.doi.org/10.1056/NEJMoa0808431. Epub 2008 Dec 17. Erratum in: N Engl J Med. 2009 Sep 3;361(10):1024-5. N Engl J Med. 2009 Sep 3;361(10):1028. PubMed PMID: 19092145. 3. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011 Mar 3;364:829e841. http://dx.doi.org/10.1056/NEJMoa1008862. Erratum in: N Engl J Med. 2011 Mar 31;364(13):1281. PubMed PMID: 21366474. 4. Gregg EW, Chen H, Wagenknecht LE, et al, Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012 Dec 19;308:2489e2496. http://dx.doi.org/10.1001/ jama.2012.67929. PubMed PMID: 23288372. 5. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014 Apr 17;370:1514e1523. http://dx.doi.org/10.1056/ NEJMoa1310799. PubMed PMID: 24738668. 6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10year follow-up of intensive glucose control in type 2 diabetes.
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N Engl J Med. 2008 Oct 9;359:1577e1589. http://dx.doi.org/ 10.1056/NEJMoa0806470. Epub 2008 Sep 10. PubMed PMID:18784090. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367:309e318. http://dx.doi.org/10.1056/NEJMoa1203859. Epub 2012 Jun 11. PubMed PMID: 22686415. Pan XR, Li GW, Hu YH, 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;20:537e544. PubMed PMID: 9096977. Patel A, , ADVANCE Collaborative Group, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007 Sep 8;370:829e840. PubMed PMID: 17765963. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006 Feb;49:289e297. Epub 2006 Jan 4. PubMed PMID: 16391903.
11. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR. SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009 Mar 5;360:961e972. http://dx.doi.org/10.1056/NEJMoa0804626. Epub 2009 Feb 18. 12. Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, ONTARGET and TRANSCEND Investigators. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation. 2011 Mar 15;123:1098e1107. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.964171. Epub 2011 Feb 28. PubMed PMID: 21357827. 13. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503e2515. 14. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009 Nov;52:2288e2298. http://dx.doi.org/ 10.1007/s00125-009-1470-0. Epub 2009 Aug 5. 15. UK Prospective Diabetes Study Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837e853.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/jicc
Glycemic control for macrovascular disease in type II diabetes: Evidence and insights from recent trials Sanjay Rajagopalan Division of Cardiovascular Medicine, University of Maryland, Baltimore, MD, USA
article info Article history: Received 19 January 2015 Accepted 11 February 2015
1.
Diabetes and survival
This data is from 97 prospective studies taken from a population cohort study called the “Emergent Risk Factors Collaboration” (NEJM, 2011). This data clearly shows that the life expectancy is reduced by 6e7 years in a patient who is diagnosed with diabetes since middle age, irrespective of the gender. Most of the reduction in life years in type 2 diabetics is driven by approximately 56% contribution by vascular mortality. There is also a big contribution by non-cancer, nonvascular death but the predominant cause in mortality in the type 2 diabetic is cardiovascular complications (Fig. 1). There is underutilization of therapies in India, which is clearly the epicenter of type 2 diabetes. There will be significant advances and there have been implementation of guidelines.
2.
Event rates in type II diabetes mellitus
This research by Gregg and coworkers (Gregg et al, NEJM, 2014) observed the age-standardized rates of diabetes rate of complications in North American adults. This was taken from a variety of different sources. Some of the complications in type 2 diabetics are acute myocardial infarction, stroke, amputation, and end-stage renal disease. The reductions in these complications in type 2 diabetes over a 20-year period, from 1990 to 2010 are Nothing short of remarkable. 67% reduction in
myocardial infarction has been observed (Fig. 2). There could be a number of reasons for this: (i) individual behaviors, (ii) diet, (iii) activity, (iv) use of pharmacologic therapies, (v) implementation of guidelines, and (vi) systems based approaches for the management of type 2 diabetes. Hopefully, this will also happen in India in the years to come with appropriate implementation of multifactorial strategies. Fig. 3 depicts the occurrence of cardiovascular event rates as observed in various trials of diabetes. UKPDS is a trial that was designed in the 1970s or 1980s, and a more contemporary trial like ORIGIN. Both these studies were quite similar, since both of them recruited new-onset type 2 diabetics, people with impaired fasting glucose and glucose intolerance. A significant reduction in annual event rates in these 2 trials can be picked up immediately. A similar trend is also seen in contemporary clinical trials for revascularization in type 2 diabetes such as FREEDOM which is a contemporary clinical trial, compared with BARI 2D (Fig. 4). The cause of reductions in cardiovascular events in the type 2 diabetics in the western hemisphere and the change in baseline risk factors are attributable to the usage of pharmacologic strategies which are very effective. That is the message that needs to be emphasized. The UKPDS trial that randomized new-onset type 2 diabetics, roughly within 3 years of the diagnosis to an intensive glucose lowering strategy, either using sulfonylureas or insulin or comparatively less intensive strategy. The endpoint in UKPDS was a composite endpoint of every conceivable complication of type 2 diabetic. This actually turned out to be a very useful way to look at this because measurement of all complications in type 2 diabetics is possible. The risk for type 2 diabetics is more than merely cardiovascular risk; it includes microvascular complications such as nephropathy, and retinopathy. It also includes myocardial infarction, stroke and amputation for peripheral vascular disease. Any diabetes-related endpoint was reduced with the usage of intensive insulin-based
E-mail address: [email protected]. http://dx.doi.org/10.1016/j.jicc.2015.03.006 1561-8811/Copyright © 2015, Indian College of Cardiology. All rights reserved.
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Fig. 1 e Survival data from 820,900 individuals in 97 prospective studies. Source: Seshasai SR, et al. N Engl J Med. 2011; 364(9):829e841
treatments. The majority of risk reduction with intensive treatment of glucose in UKPDS was driven by microvascular complications. The confidence intervals for myocardial infarction actually crossed unity, suggesting that it was not statistically insignificant (Fig. 5). At the end of 2000, after the results of UKPDS were announced, the relationship between microvascular disease and HbA1c was established. The risk keeps going down with
reducing levels of HbA1c, all the way down to less than 6 (Fig. 6). According to the guideline committee there was no robust evidence for target of HbA1c less than 7, but the continuing relationship between HbA1c reduction in the UKPDS shows that risk reduction continues to HbA1c levels of less than 6%. Maybe an extension of this recommendation is needed, and starting recommendation to target HbA1c levels of less than 7
Fig. 2 e Trends in age-standardized rates of diabetes-related complications in U.S adults. Source: Gregg EW et al. NEJM. April 17, 2014; 370; 1514e1523
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Fig. 3 e Annual event rate due to coronary heart disease and MI observed in various diabetes trials.
Fig. 4 e Comparison of the BARI 2D and the SYNTAX trials, in terms of CV events.
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is probably good. This is the basis of recommendation dating back to 2000 and various guideline societies have continued to suggest till date, lowering HbA1c to less than 7 might be beneficial from a microvascular perspective. The curve is much more flat for myocardial infarction as shown in Fig. 6. UKPDS clearly suggested that for every 1% reduction in HbA1c, there was a 21% reduction in diabetes rated deaths, and 37% reduction in microvascular endpoints. Incremental lowering in HbA1c was interpreted as being beneficial for patients. “As low as you can get” was probably the view of the world back in the early 2000s. But it was quickly realized that HbA1c just like blood pressure has limitations. Lower levels of HbA1c not surprisingly were associated with a higher risk of hypoglycemia (Fig. 7). There is a limit to which the HbA1c can be lowered, and the question is what is that limit and does that vary for a particular patient. Although the microvascular complications go down in about 4 years' time, but regarding macrovascular disease, there was no robust evidence. Appropriately powered clinical trials such as ACCORD, ADVANCE, or VA-DT were designed, keeping this factor in mind. Fig. 7.1 shows the baseline HbA1c for these 3 trials. ADVANCE aimed at bringing the HbA1c to less than 6.5%, and ACCORD aimed for lower HbA1c of 7.9% and 6% (depending upon the group). VADT set a more conservative goal HbA1c of 7%. These are relatively large studies but the median duration follow-up was approximately 4e6 years, 5.6 years for VA-DT (Fig. 7.2).
Fig. 5 e Blood glucose levels and vascular risk in diabetes e Best Evidence. (Diabetes Related End-Points: Sudden death, death from hyperglycemia or hypoglycemia, fatal or non-fatal MI, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous hemorrhage, retinal photocoagulation, blindness in one eye, or cataract extraction). Source: UK Prospective Diabetes Study Group. Lancet. 1998; 352(9131):837e853
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Fig. 6 e Blood glucose and vascular risk in diabetes best evidence: 2000. Source: Stratton IM, et al. BMJ. 2000; 321(7258):405e412
There were higher rates in mortality in the intensive treatment arm in the ACCORD trial, and it was stopped prematurely at 3.6 years. ADVANCE was different because the endpoint was a combination of microvascular and macrovascular endpoints, just like UKPDS, and it was a positive study. There was a reduction in the primary endpoint in ADVANCE. In VA-DT, there was no change in a very similar endpoint to ACCORD (death plus myocardial infarction). All of these trials showed an increase in hypoglycemia with intensive insulin regimens. Fig. 8 provides the summary of all of this information. Microvascular disease is exquisitely sensitive to glycemia control and if a drug lowers HbA1c, it might lower microvascular complications. Cardiovascular risk reduction seems to be evident, at least in the follow-up studies when the patients are followed up for long term beyond the trial duration. Keeping in mind that all these trials are 5 years and following up the patients for a much longer duration like 10 years, there might be differences in cardiovascular disease. This is certainly the case with a long-term 10 year follow-up of UKPDS and the long-term follow-up of DCCT/EDIC (trial in type 1 diabetes). Both of these trials show that if patients are followed long enough, a benefit in cardiovascular disease will be seen. The long-term follow-up was in the positive 33% reduction in the metformin arm in UKPDS with the follow-up.
3.
Hypoglycemia as a risk marker
Hypoglycemia was a problem and all of these trials consistently show that induction of major hypoglycemia in a patient with type 2 diabetes is a risk factor for future cardiovascular events (Figs. 9 and 10). If a patient is prone to hypoglycemia, avoidance of aggressive glycemia lowering for obvious reasons and from a cardiovascular perspective is advisable. There is approximately a 2-1/2 fold increase in hazard ratio for cardiovascular events if hypoglycemic events are frequent. This is also seen in the post-hoc analysis, which shows that if hypoglycemia develops even within a 3-month period or a 6month period, there was a very strong association with
predisposition to macrovascular events and death from any cause. They point very robust signals by 3-1/2 fold increase or death from cardiovascular causes. Hypoglycemia, therefore, is an adverse risk prognosticator for cardiovascular reasons. There is a variety of different mechanisms that have been postulated, namely, sympathetic imbalance, vagal imbalance, etc.
4. Legacy and vintage effects in diabetes mellitus The other important concept that needs to be understood is the concept of legacy. This is important in the Indian context because there were several questions pertaining to statin therapy in type 2 diabetics and do we stop glycemia lowering after a certain duration and do these effects persist? For instance, consider a patient who participated in a clinical trial, and treated for 2- to 3-year period or a 4-year period and eventually, the trial patients went back in the usual behavior where they were not rigorously controlled anymore. The beneficial effects of this treatment might persist for as long as 10 years after stopping the therapy. This phenomenon of lasting beneficial effects of interventions done early in the course of disease is what the endocrinologists refer to as the “legacy effect”. There is a legacy of treatment effect that you divine many years after treatment which is certainly seen in type 2 diabetics. That is not to say that treatment should stop. It just goes to show that the treatment effects over time can persist; and really underscores the importance of treatment early on so that the treatment benefits coming on board several years down the line after starting treatment. The other concept was out of vintage which refers the duration of type 2 diabetes, and to what extent treatment has affected the course of the disease. This is a long-term follow-up of UKPDS. During the shortterm, there was no signal for macrovascular events, but on long term follow-up for 10 years, the HbA1c curves converge. In other words, they were no different between intensive
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Fig. 7 e Benefit and risks of blood glucose control coexist: Evidence from UKPDS. The risks of diabetes complications significantly reduced for every 1% reduction of HbA1c. 1: Glycemia trials in perspective. 2: Glycemic targets set by various trials.
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Fig. 8 e Impact of intensive therapy for diabetes: Legacy and vintage effects for CV events.
glycemia lowering group and the usual conventional care group. Despite the HbA1c becoming convergent, there was a benefit in terms of mortality; 13% reduction in mortality at 10 years, at the end of participating in UKPDS. There is also a reduction in myocardial infarction (Fig. 11). In the patients that participated in long duration trials like VA-DT and ACCORD, it might not be possible to see changes in
myocardial infarction within a 5-year duration. A longer duration would be needed. In some cases, the disease has progressed so far, that a reduction in macrovascular events might not be possible. This has implications for design of clinical trials. Historically, clinical trialists were of the opinion to include the sickest patients in clinical trials since the sample size can be lower and the studies can be sufficiently powered. These patients are going to have events but these are precisely the type of patients where a reduction in cardiovascular events may not be seen because of the problem of “vintage” effect (Fig. 12). Fig. 13 shows the UKPDS patient population with recentonset type 2 diabetes, in whom lowering of glucose was done aggressively. They didn't have bad plaque memory or much of atherosclerosis since they are recent-onset type 2 diabetics. Contrast that with somebody participating in ACCORD, ADVANCE, and VA-DT; they have a lot of biologic memory. In other words, they have a lot of plaque with complications. In such patients, even if the HbA1c is driven down aggressively, a significant reduction in cardiovascular events may not be seen.
Fig. 9 e Hypoglycemia in the landmark trials. Source: Turnbull FM, et al. Diabetologia. 2009;52(11):2288e2298
Fig. 10 e Incident vascular outcomes and death among patients who had severe hypoglycemia in ADVANCE. Source: Zoungas N,et al. Engl J Med. 2010 Oct 7; 363(15):1410e8
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Fig. 11 e 10 year follow-up of UKPDS. Source: Holman R et al. N Engl J Med 2008; 359:1577e89
5.
Multifactorial intervention
Interventions of lifestyle choices, physical activity, will have huge benefits in terms of changing incidence, very dramatically, and very soon. Small amounts of weight loss makes a huge difference in insulin sensitivity as has been demonstrated repeatedly in multiple studies. It is no surprise that
lifestyle intervention in the short term is highly effective in reducing propensity to development of type 2 diabetes. This has been an international experience, irrespective of the country, the Da Qing study in China (Pan et al, Diab Care, 1997), the Indian Diabetes Prevention Program (Ramachandran A, diabetologia, 2009). Many of these trials also show long-term reductions and in follow-up. For instance, a 20-year follow-up of the Chinese diabetes study shows a 43% reduction in type
Fig. 12 e Effect of duration of diabetes (“vintage”) and other pre-specified sub-groups on major cardiovascular events. Source: Turnbull FM, et al. Diabetologia. 2009; 52(11):2288e2298
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Fig. 13 e Heart disease prevention with improved glycemic control: Start early and continue long-term.
Fig. 14 e Steno-2: Effects of multifactorial intervention on CV outcomes. Source: Gaede P, et al. N Engl J Med. 2008; 358(6):580e591
2 diabetes which is pretty remarkable. In a country like India, these are extremely cost effective interventions, and there is no question that lifestyle choices or lifestyle intervention trials are at the core of the treatment of type 2 diabetes. Indeed,
Weight loss of greater than 7% in exercise is fundamental in the treatment approach (Gregg et al, 2012, JAMA). The Steno-2 is probably one of the smallest studies that showed such remarkable benefits. The one remarkable thing
Fig. 15 e Effect of early intensive therapy on outcomes detected by screening. Source: Griffin SJ, et al. Lancet. 2011;378(9786):156e167
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Fig. 16 e Summary of pharmacological incretin action on different target tissues.
that Steno-2 did, that many of the other more contemporary multifactorial intervention trials did not do was smoking cessation. It is a very important part of intervention, but smoking, including secondhand smoke, continues to be a major risk factor. This is intervention is particularly important in type 2 diabetics (Fig. 14).
This type of intervention when extrapolated to contemporary European sites, results are much less effective compared to Steno-2 (Fig. 15). This doesn't argue against risk factor modification and aggressive control, but the fact that it takes a lot to reduce risk in type 2 diabetics. If it is to be done along with other interventions like smoking cessation in a
Fig. 17 e Macrovascular outcome trials.
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Fig. 18 e SAVOR-TIMI primary outcome measure. Source: Scirica BM, et al.N Engl J Med. 2013 Oct 3;369(14):1317e6 and AHA Scientific Session, 2013
Fig. 19 e 1: SAVOR-TIMI: Individual Endpoints of Secondary Composite End-Point: Expanded MACE. 2: SAVOR-TIMI: Risk of hospitalization for HF according to baseline NT-proBNP. Source: Scirica BM, et al.N Engl J Med. 2013 Oct 3;369(14):1317e6 and AHA Scientific Session, 2013
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patient population with high prevalence of risk factors such as smoking, a very remarkable effect can be obtained.
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in a lot of debate about whether this is a class effect or the DPP-4 inhibitors cause heart failure, which this remains to be determined. Certainly, the signals have been raised with Saxagliptin, not with Alogliptin.
6. how you lower glucose does make a difference 7. This takes us back to the first question. Not all drugs are created equal. There could be a drug that is remarkably effective in lowering HbA1c but it might have an adverse effect on mortality. The example of this would be a recent drug which is a PPARalpha, PPAR-gamma activator. The idea is if we could combine the pioglitazone with a fibrate like fenofibrate and come up with a combination molecule, we could get the benefits of PPARalpha agonism and also PPAR-gamma agonism. As opposed to pioglitazone, which shows the benefit, something like aleglitazar (combined PPAR-alpha and gamma agonist) is very effective in reducing HbA1c but it actually increases mortality. It reduces HbA1c, triglycerides, and it increases HDL cholesterol, a modest effect in increasing LDL cholesterol, but it increased heart failure, fractures, GI complication rate. The ORIGIN trial compared insulin glargine versus standard care. The primary endpoint was a hazard ratio of 1.02 for mortality in cardiovascular events. Soon after treating 6e7 years, normalizing plasma glucose with insulin glargine, reducing HbA1c, reducing fasting glucose does not seem to have an effect on cardiovascular mortality. In fact, this is associated with more weight gain and hypoglycemia. The newest drugs in the market are the DPP-4 inhibitors and incretin-based therapies, and all clinicians are waiting with bated breath to find out more about GLP-1agonist. They lower HbA1c on an average by about 0.8e1%, they lower weight. They also seem to have some favorable effects in blood pressure, but the question is they lower cardiovascular mortality? As seen in Fig. 16, the effects of incretin-base therapies seem to be all the right things. The question is whether these changes in surrogate measures including glycemia control translate into reduction in cardiovascular events and Fig. 17 summarizes all of the outcome trials. These include the EXAMINE study (primary safety study) that included patients with acute coronary syndrome, randomized them to Alogliptin versus placebo and evaluated the safety. There was no difference in terms of cardiovascular death, nonfatal myocardial infarction, and stroke in the Alogliptin, as compared to placebo. There was no difference between the 2 groups and the treatment was safe. But this did not meet the superiority, a secondary hypothesis. There was also a recent concern about heart failure with these patients. A post-hoc pre-specified analysis of composite endpoint inclusive of hospitalized heart failure in the Alogliptin versus placebo was done, and the P-values are non-significant. There was a little bit of trend towards increases in heart failure cases but this was not borne out in subsequent analyses. Another trial was the SAVOR-TIMI trial, which compared Saxagliptin with placebo. The primary endpoint in this trial was a superiority analysis, which this trial did not meet (Fig. 18). The interesting thing was in this study; hospitalization for heart failure which is again a pre-specified secondary endpoint was higher by approximately 27% in the Saxagliptin arm compared to placebo (Fig. 19.1 and 19.2). This has resulted
Conclusion
Lowering glucose reduces microvascular complications within a 5-year time window, macrovascular events might take a longer duration. Drugs used to accomplish glycemic control may have independent effects, which is why the regulatory authorities have mandated cardiovascular safety trials. Just because the drug reduces HbA1c does not necessarily make it effective to lower cardiovascular complications. This must be done for any new drug undergoing evaluation. DPP-4 inhibition appears to be cardioprotective from a preclinical perspective.
Conflicts of interest The author has none to declare.
Acknowledgement I would like to acknowledge efforts of Dr. Rishi Jain and Dr. Medhinee Kulkarni for their assistance in drafting this manuscript.
further reading
1. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358:2545e2559. http://dx.doi.org/10.1056/ NEJMoa0802743. Epub 2008 Jun 6. PubMed PMID: 18539917. 2. Duckworth W, Abraira C, Moritz T, et al, VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009 Jan 8;360:129e139. http:// dx.doi.org/10.1056/NEJMoa0808431. Epub 2008 Dec 17. Erratum in: N Engl J Med. 2009 Sep 3;361(10):1024-5. N Engl J Med. 2009 Sep 3;361(10):1028. PubMed PMID: 19092145. 3. Emerging Risk Factors Collaboration, Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011 Mar 3;364:829e841. http://dx.doi.org/10.1056/NEJMoa1008862. Erratum in: N Engl J Med. 2011 Mar 31;364(13):1281. PubMed PMID: 21366474. 4. Gregg EW, Chen H, Wagenknecht LE, et al, Look AHEAD Research Group. Association of an intensive lifestyle intervention with remission of type 2 diabetes. JAMA. 2012 Dec 19;308:2489e2496. http://dx.doi.org/10.1001/ jama.2012.67929. PubMed PMID: 23288372. 5. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014 Apr 17;370:1514e1523. http://dx.doi.org/10.1056/ NEJMoa1310799. PubMed PMID: 24738668. 6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10year follow-up of intensive glucose control in type 2 diabetes.
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N Engl J Med. 2008 Oct 9;359:1577e1589. http://dx.doi.org/ 10.1056/NEJMoa0806470. Epub 2008 Sep 10. PubMed PMID:18784090. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367:309e318. http://dx.doi.org/10.1056/NEJMoa1203859. Epub 2012 Jun 11. PubMed PMID: 22686415. Pan XR, Li GW, Hu YH, 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;20:537e544. PubMed PMID: 9096977. Patel A, , ADVANCE Collaborative Group, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007 Sep 8;370:829e840. PubMed PMID: 17765963. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V, Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006 Feb;49:289e297. Epub 2006 Jan 4. PubMed PMID: 16391903.
11. Serruys PW, Morice MC, Kappetein AP, Colombo A, Holmes DR. SYNTAX Investigators. Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease. N Engl J Med. 2009 Mar 5;360:961e972. http://dx.doi.org/10.1056/NEJMoa0804626. Epub 2009 Feb 18. 12. Tobe SW, Clase CM, Gao P, McQueen M, Grosshennig A, ONTARGET and TRANSCEND Investigators. Cardiovascular and renal outcomes with telmisartan, ramipril, or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. Circulation. 2011 Mar 15;123:1098e1107. http://dx.doi.org/10.1161/CIRCULATIONAHA.110.964171. Epub 2011 Feb 28. PubMed PMID: 21357827. 13. The BARI 2D Study Group. A randomized trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med. 2009;360:2503e2515. 14. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009 Nov;52:2288e2298. http://dx.doi.org/ 10.1007/s00125-009-1470-0. Epub 2009 Aug 5. 15. UK Prospective Diabetes Study Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837e853.