Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study

BMJ 2000; 321 doi: http://dx.doi.org/10.1136/bmj.321.7258.405 (Published 12 August 2000)
Cite this as: BMJ 2000;321:405

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UKPDS35 [1] a publication of United Kingdom Prospective Diabetic Study (UKPDS) concludes that there is a direct relation between the risk of complications of diabetes and glycaemia over time. How ever unadjusted complication rates provided in the table2 of the paper shows a significant variation from the above mentioned pattern at very high HbA1c values. In fact mortality rates and myocardial infarction [MI] rates are lower for HbA1c >10% group compared to few other groups with better glycimic control. UKPDS35 introduces an adjustment to this abnormal variation by applying a statistical technique which focuses on white men aged 50 to 54. How ever a more meaningful correction is necessary and seems to be available to explain the true nature of variation in complications with glycimic control applicable for the Type 2 diabetic patients.

Most of the UKPDS reports including its main report UKPDS33 [2] and UKPDS35 do not differentiate the LADA patients from the Type 2 diabetic patients. How ever 9•4% of the patients included in the randomized sample had LADA [3]. As LADA is different from Type 2 diabetes, almost all of them will have high HbA1c ratings unless they were provided with sufficient quantity of insulin. Protocol adopted in the UKPDS has directed LADA patients in the conventional groups to keep Fasting Plasma Glucose(FPG) values closer to 15 even after converting them into sulfonylurea or insulin [4].

Fast response to UKPDS41 [5] provides a simple method of separating total diabetes related complications in to two groups named as latent autoimmune diabetes in adults (LADA) group and Type 2 diabetes group. The method assumes in spite of LADA patients having relatively higher micro vascular complications but lower macro vascular complications, the combined affect will produce more or less similar number of total complications compared to Type 2 diabetic patients. As the abnormal variation patterns appearing in UKPDS35 are related to macro vascular deceases where complication rates are significantly different additional factors should be considered to obtain a more meaningful result.

UKPDS66 [6] provides the simple risk factors and their sensitivities derived from the trial sample applicable to fatal myocardial infarction. MI risk increases with age, HbA1c %, systolic blood pressure (SBP) and the period elapsed after diagnosis. Although the sensitivities to these parameters are not linear, cumulative effect of above parameters is governed by the arithmetic sum of four figures each one representing one of the identified risks. Figure representing the affect of a risk is computed by multiplying the actual parameter by corresponding sensitivity coefficient (coefficients for fatal MI as given in the UKPDS66 are, Age : 0.048, HbA1c: 0.178, SBP: .0141. Although the non fatal MI sensitivity parameters can be some what different, their relative values should be similar. Therefore above figures will be used as general MI risk sensitivity coefficients). As the post detection period does not vary with the type of disease it will not be considered in the current discussion.

UKPDS70 provides the comparative details of LADA and Type 2 diabetic patients included in the trial. LADA patients were 4.5 years younger and their SBP values were 7 units lower compared to Type 2 diabetic patients. (LADA age 48.2: SBP 129, Type 2 diabetic patients age 52.7 : SBP 136).

As shown in the fast response to UKPDS41 LADA patients in the conventional treatment group had HbA1c value closer to 10% and LADA patients in the intensive control group had low HbA1c values? As a consequence of above findings it can be concluded that there cannot be many LADA patients with intermediate level of HbA1c values. In other words patients having medium level of HbA1c values should be Type 2 diabetic patients.

Therefore change of complication rate applicable for HbA1c change from 7-8 range to 8-9 range represents a property of Type 2 diabetic patients included in the sample. However change of complication rate applicable for HbA1c change from 9-10 to 10+ has got influenced by the presence of LADA patients. In fact this is the range that shows reverse trend or reduction in some of the very important complication rates such as MI and diabetes related death with increased HbA1c %.

Although the sample selected in the UKPDS35 is a sub set of total UKPDS trial, patients were not selected by any special qualifying criteria. Therefore they should have more or less same properties as the UKPDS total group.

UKPDS had 1138 patients in the conventional treatment group. As 9.4 % of them had LADA there should be 107 LADA patients in the conventional treatment group. As there were 5102 patients in the total group 2.097% of them were LADA patients assigned to the conventional treatment.

MI patient years in UKPDS35 sample were 42880 (can be obtain by adding patient years of different sub groups). If LADA patients and Type 2 diabetic patients had similar survival rates then LADA patient years in conventional treatment group computed according to above % is 899. How ever according to UKPDS70 availability of LADA patients at the end of 10 years were 10% higher compared to type 2 diabetic patients( 51% LADA patients: 46% Type 2 diabetic patients). Therefore it is more correct to apply a 5% upward revision to above figure to accommodate the increase in recorded LADA patient years due to higher availability for monitoring. As a result of above correction number of LADA patient years becomes 944.

Total patient years applicable for the HbA1c >10 range for MI is 1490. Therefore reasonable part of the patient years counted under HbA1c >10 range should be LADA patient years. (If 50% of the LADA patients had HbA1c >10 then 472 LADA patient years are included in the HbA1c>10 range patient years. This represents 31.7% of the total patient years of the highest HbA1c category. Actual % of LADA patient years in the HbA1c>10 range is likely to be much higher.)

As LADA patients were younger and had lower SBP values their MI complication rate is much less. From the sensitivity parameters given in the UKPDS66 it is quite clear MI complication rate of the average LADA patient with HbA1c % closer to 10 is much less compared to a Type 2 diabetic patient with HbA1c% closer to 9 , This happens because LADA patients are younger and they had lower SBP. As an example when HbA1c increase of 1, age decrease of 4.5 and SBP decrease of 7 will result in a reduction in the cumulative risk indicating figure [arithmetic addition (- .1367)= HbA1c factor(+.178)+age factor(-.216)+ SBP factor(-.0987)]

Above calculation clearly shows that presence of LADA patience has distorted the picture of relationship between complication rates and HbA1c % variation. How ever in addition to SBP, HbA1c%, Age and period after diagnosis, type of illness should also be considered as a separate risk factor. Actually sensitivity factors applicable for LADA can be significantly different from the sensitivity factors applicable for Type 2 diabetes. It is to be noted that the sensitivity factors used here were derived from the mixed sample and they should be different from the actual factors corresponding to LADA and Type 2 diabetes both.

Actual pattern variation should have got influanced by the well known property of LADA patients having less macro vascular complications. As these patients does not have problems related to excess insulin net reduction in macro vascular complications should be much higher than the computed result representing the effect of SBP, Age and HbA1c only.

As mentioned earlier UKPDS70 clearly indicates that percentage of LADA patients available for follow up at 10 years were higher compared to Type 2 diabetic patients. Considering the probability of dropout by other factors to be equal it can be concluded that death rate of LADA patients is much lower compared to the Type 2 diabetic patients. In fact this conclusion is strongly related to the findings of UKPDS35 and the above discussion.

Presence of LADA patients should have affected all the complication types. As discussed earlier it is a different decease. Categorizing their properties separately will help to design better treatment options to both patient groups. As the LADA patient percentage is much higher than Type 1 patient percentage in many communities separation of UKPDS35 data in to two groups should be considered as a priority. To collect such a volume of data from a new study will take a long time.

References

1. Stration M IM, Adlet AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35) BMJ 2000 321:405-12.

2. UKPDS Group (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. (UKPDS 33) Lancet 352:837-853

3. Davis TM Wright AD, Mehta ZM et al (2005) Islet autoantibodies in clinically diagnosed type 2 diabetes: prevalence and relationship with metabolic control (UKPDS 70). Diabetologia 48:695-702

4 UKPDS Group (1991)UK Prospective Diabetes study (UKPDS) VIII Study design, progress and performance. Diabetologia 34:877-890

5. LADA patients in the UKPDS sample has influenced the ukpds41 conclusion: Arya K Kumarasena : Rapid Response to Cost effectiveness of an intensive blood glucose policy in patients with type 2 diabetes: economic analysis alongside randomised controlled trial (ukpds 41). Gray a,Raikou M, McGuire A et al(2000). BMJ 320:1373-13

6. Stevens RJ Coleman RL Adler AI Stratton IM Matthews DR Holman RR (2004) Risk Factors for Myocardial Infarction Case Fatality Type 2 Diabetes. Diabetes Care 27:201-207

Competing interests: None declared

Competing interests: None declared

Arya K Kumarasena, Consultant/Director

Metropolitangroup of companies 85 Braybrook place Colombo2 Sri Lanka. SRICL2

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12 October 2000

Editor - Articles recently published in BMJ (UKPDS 35 & 36)1,2 by the UKPDS group appear methodologically problematic, and are inadequately reported.

It appears the authors followed analytical procedures used previously for type 1 diabetes data from the DCCT3, involving proportional hazards and Poisson regression models of the relative risks of developing diabetic complications due to lifetime exposure to hyperglycaemia and hypertension.

However, there are important differences between the two studies with consequences for their analysis. In particular, in the DCCT cohort there were insufficient events to allow any analysis of either macrovascular complications or mortality: results were only reported for three microvascular endpoints.

Sadly, insufficient information is provided in the UKPDS papers to allow full assessment of the statistical models obtained. Nonetheless, the limited detail supplied suggests that diabetes-related mortality risk increases considerably faster than all- causes mortality with both HbA1c and SBP, so that all non-diabetic mortality ceases for patients with HbA1c > 13% or SBP >186mm Hg. Clearly this is unrealistic and casts doubt on the appropriateness of this model formulation for mortality. A competing risks model, with non-diabetes related deaths assumed to be independent of both glycaemia and blood pressure, would be preferable. We have estimated such models using both linear and log-linear equations for diabetes-related mortality risk, and obtain plausible relationships consistent with the published data and credible for all values. If the DCCT approach fails for mortality, it also unlikely to work for macro- vascular disease generally, the dominant cause of diabetes-related mortality.

Use of lifetime exposure to glycaemia and blood pressure as principal independent variables in the analyses implies a very strong general assumption on the nature of incidence and progression of diabetic complications. Though reasonable to consider that microvascular damage accumulates continuously over time, in the case of heart disease and stroke there are probably different mechanisms operating in the development of chronic disease, incidence of acute events, and case fatality rates so that current values of clinical variables may be at least as influential as accumulated exposure. There is merit in exploring a range of alternative exponentially-smoothed independent variables.

Another consequence of using updated mean HbA1c in regression models is that incremental risk ratios reported in Table 3 are not comparable with those shown for the equivalent baseline variables. The linear upward trend in glycaemia observed in the trial means that models using a cumulating-average mean variable will generate risk gradients approximately double those obtained with single observations. Thus from a clinical perspective, the models which use updated mean HbA1c significantly overstate the risk gradient. Most disturbingly, these publications give no details of the statistical models employed, by which other researchers may judge their appropriateness and reliability, in stark contrast to the DCCT study which presented full diagnostics of their models.3 Though such information may not be relevant to all BMJ readers, it could have been provided as an eBMJ appendix, or a supplement obtainable from the authors. At present the Diabetes Trial Unit at Oxford is refusing to release such details to individual researchers, and it is a matter of regret that custodians of a major trial database, largely funded from public sources, seem unwilling to make the fruits of their work more freely available for scrutiny by the wider academic and clinical community.

Adrian Bagust
Deputy Director,
York Health Economics Consortium, University of York, UK.

References

1 Stratton IM, Adler AI, Neil HAW, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321:405-12.

2 Adler AI, Stratton IM, Neil HAW, Yudkin JS, Matthews DR, Cull CA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 2000; 321:412-9.

3 DCCT Research Group. The relationship of glycaemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44:968-83.

Competing interests: None declared

Adrian Bagust

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Stratton, et. al. have documented that as glycaemic exposure increases, diabetic complications increase.(1) They conclude that treatment of hyperglycemia will have substantial benefit, a conclusion reiterated by Dr. Tuomilehto.(2) Yet reduction of glycaemic exposure failed to have such benefit in the UKPDS randomized trial (3, 4) For example, Stratton's data would suggest that reducing mean HgA1C by 1% would reduce diabetes related deaths by 21%. Intensive treatment of hyperglycaemia for 10 year in UKPDS reduced HgA1C by nearly 1% (from 7.9 to 7.0%), yet failed to reduce diabetes-related deaths significantly. The conventionally treated group, with greater glycaemic exposure, suffered diabetes-related deaths at a rate of 11.5 deaths/1,000 person-years. Based on Stratton's data, the intensively treated group should have experienced diabetes-related death at a rate of 9.0 deaths/1,000 person- years. However, intensive treatment was associated with only a non- significant decrease in diabetes-related mortality.(4) Similarly, Stratton's data suggests that intensive treatment would result in significant reductions in adverse outcomes that include all-cause mortality, stroke, myocardial infarction, and amputation. Reducing HgA1C by nearly 1% in the UKPDS, however, was not associated with significant reductions in any of these adverse outcomes.

Thus, treatment that significantly improves glycaemic control does not achieve the predicted benefit. Does this mean that greater glycaemic exposure is a marker for adverse outcomes--but not a cause? This would imply that the higher the HgA1C, the more one needs to pay attention to non-glycemic treatment of diabetic patients--such as controlling blood pressure. Or does it mean that the treatments currently available to lower glucose harm diabetic patients as much as the lowering of blood glucose helps them?

I wonder if McCormack and Greenhalgh are correct when they suggest that metformin treatment improves outcomes in diabetic patients, not necessarily resulting from its glucose lowering effect, but that lowering glucose per se is of little to no value in type 2 diabetes.(3)

(1)Stratton IM, Adler AI, Neil AW, et. al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321:405-412.

(2)Tuomilehto, J. Controlling glucose and blood pressure in type 2 diabetes. BMJ 2000;321: 394-395.

(3)McCormack J, Greenhalgh T. Seeing what you want to see in randomised controlled trials: versions and perversions of UKPDS data. BMJ 2000;320:1720-1723.

(4)UKPDS Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes Lancet 1998;352:837-853.

Competing interests: None declared

Brian Budenholzer

Group Health Cooperative; Spokane, WA; USA

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