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Microvascular Residual Risk Studies

25 September 2014
Statins and microvascular risk
While this analysis showed that statin use was not associated with an increased risk of some diabetic microvascular complications, treatment did not prevent their development over the 2.7 year median follow-up period.
Nielsen SF, Nordestgaard BG. Statin use before diabetes diagnosis and risk of microvascular disease: a nationwide nested matched study. Lancet Diabetes Endocrinol 2014; [Epub ahead of print, September 10, 2014].
Objective: To test whether statin use increases the risk of diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, and gangrene of the foot in individuals with diabetes
Study design: Nationwide nested matched study
Study population:

Individuals living in Denmark aged ³40 years and diagnosed with new-onset diabetes between Jan 1, 1996, and Dec 31, 2009 were included; 15,679 who had used statins regularly until their diagnosis of diabetes (statin users) were matched in a 1:3 ratio with 47,037 individuals who had never used statins before diagnosis (non-statin users).

Primary endpoint:

• Cumulative incidence of diabetes microvascular complications (diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, or gangrene of the foot).


Data were analysed using Cox regression models, adjusted for covariates including sex, age at diabetes diagnosis, and method of diabetes diagnosis. Potential biases between statin users and non-statin users, were addressed by adjustments using a propensity score.


Over a median follow-up of 2.7 years (range 0–13 years), 2,866 patients developed diabetic retinopathy, 1,406 developed diabetic neuropathy, 1,248 developed diabetic nephropathy, and 2,392 developed gangrene of the foot. Hazard ratios for each microvascular complication (statin users versus non-statin users) are summarised in Table 1.

Table 1. Risk for diabetic microvascular complications (statin users versus nonstatin users).

Diabetic complication

Hazard ratio (95% CI)


Diabetic retinopathy

0·60 (0·54–0·66)


Diabetic nephropathy

0.97 (0.85–1.10)

NS, 0.62

Diabetic neuropathy

0·66 (0·57–0·75)


Gangrene of the foot

0·88 (0·80–0·97)


Authors’ conclusion: Use of statins before diagnosis of incident diabetes was not associated with an increased risk of microvascular disease. Whether statins are protective against some forms of microvascular disease—a possibility raised by these data—will need to be addressed in other studies similar to this, in mendelian randomisation studies, and preferably in randomised controlled trials.


The results of this analysis imply that statin use is not associated with an increased risk of diabetes-related microvascular complications, specifically the risk for diabetic retinopathy, diabetic neuropathy and gangrene of the foot. Statin use had no benefit on diabetic nephropathy. 

Undoubtedly, the size, quality and coverage of the national registry are strengths of this study. Moreover, the finding that statin use was associated with an increased risk of diabetes (1·17, 1·14–1·21; p<0·0001), was consistent with other analyses which have shown a link between diabetes and risk for incident diabetes,1,2 and thus provides an external validity to the study. Despite this, there are a number of issues, notably the lack of data on important predictors of microvascular disease, such as HbA1c, urine albumin, blood pressure, as well as lipids. There are also issues with the definition of microvascular endpoints. Notably, gangrene of the foot is defined as one diabetes-related microvascular endpoint. However, impaired tissue perfusion in the extremities in patients with diabetes, resulting in development of gangrene, receives contributions from both microvascular and macrovascular disease.3

It is important to note that statins had no effect on the risk for diabetic nephropathy. This is not inconsistent with some studies, although some have suggested a slowing in the decline of estimated glomerular filtration rate in diabetes patients.4,5 Other lipids beyond LDL cholesterol are also implicated. Indeed, the recent REALIST Micro study showed a robust association between elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), components of atherogenic dyslipidaemia, and risk for diabetic kidney disease.6 These findings build on a growing body of evidence linking triglycerides and HDL-C, with risk for diabetic microvascular complications. Statins are undoubtedly effective in lowering low density lipoprotein cholesterol and have modest effects on triglycerides and HDL-C, translating to macrovascular benefit in patients with atherogenic dyslipidaemia, as shown by the 4S study.7 However, other lipid-modifying treatments, such as peroxisome proliferator activated-receptor alpha agonists, have greater efficacy in lowering triglycerides, and this may be implicated in preventive effects in risk for diabetic kidney disease, as suggested by REALIST Micro.6

Finally, a key point which is overlooked by this paper is that statin therapy does not prevent the development of microvascular complications in diabetes patients. Over the median follow-up of 2.7 years, 3% of statin users developed diabetic retinopathy, and 2% each developed diabetic neuropathy or diabetic nephropathy. Even with optimal multifactorial treatment, as reported by the STENO-2 study, up to 50% of patients with type 2 diabetes show development or progression of microvascular disease.8 Thus, as indicated by the authors, there is a clear need for randomised controlled studies in this area, so as to define the optimal therapy for reducing the high residual risk of diabetes-related microvascular complications that persists despite best evidence-based therapy.

Another confounder is the fact that statin use prior to diabetes diagnosis was analysed with respect to incident microangiopathy in the years following diabetes diagnosis. Since microangiopathy cannot, by definition, arise prior to diabetes diagnosis in new-onset diabetes, the design of the study cannot address a potential protective effect of previous statins use on future microangiopathies, since the conditions to generate microvascular damage were not present over the time period during which statins were administered. An appropriate trial should test whether prolonged statin use in the presence of hyperglycaemia (i.e. subsequent to diabetes diagnosis) decreases incident microangiopathy.


1. Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375: 735–42.
2. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305: 2556–64.
3. Tesfaye S, Chaturvedi N, Eaton SE et al. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352: 341-50.
4. Colhoun HM, Betteridge DJ, Durrington PN, et al. Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 2009; 54: 810–19.
5. Shepherd J, Kastelein JJ, Bittner V, et al. Effect of intensive lipid lowering with atorvastatin on renal function in patients with coronary heart disease: the Treating to New Targets (TNT) study. Clin J Am Soc Nephrol 2007; 2: 1131–39.
6. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and HDL-cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes: A global case-control study in 13 countries. Circulation 2014;129:999-1008.
7. Ballantyne CM, Olsson AG, Cook TJ et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation 2001;104:3046-51.
8. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93.

Key words diabetes; microvascular complications; statin use; diabetic retinopathy; diabetic neuropathy; diabetic nephropathy; residual microvascular risk