Although vascular complications are a hallmark of diabetes, cerebral small-vessel disease (cSVD) in type 1 diabetes remains scarcely studied. We recently showed that cSVD is more common in individuals with type 1 diabetes than healthy control subjects and is associated with systolic office blood pressure (BP) (1). Hence, we aimed to further evaluate the impact of BP on cSVD in type 1 diabetes.
This substudy of the Finnish Diabetic Nephropathy (FinnDiane) Study aims to assess early markers of cerebrovascular disease in people with type 1 diabetes and has previously been described in detail (1). Of the 191 neurologically asymptomatic study participants, 73 volunteered for a 24-h ambulatory BP monitoring (ABPM). All participants underwent a clinical study visit, and brain MRI assessed for markers of cSVD (white matter hyperintensities, lacunar infarcts, and cerebral microbleeds) (1,2).
The 24-h ABPM was conducted in accordance with current standards (3). After ABPM-quality validation, we calculated average BP, mean arterial pressure (two-thirds of diastolic + one-third of systolic BP), pulse pressure (PP) (systolic − diastolic BP), BP variability (average real variability), and nocturnal dipping ([1 − nocturnal systolic / diurnal systolic BP] × 100%). Elevated BP and masked hypertension were defined as described by the European Society of Hypertension (3).
We observed cSVD in 20 (27.4%) participants, of whom 14 had cerebral microbleeds, 9 white matter hyperintensities, and 2 lacunes. Table 1 includes clinical characteristics as well as main results for BP measurements based on presence or absence of cSVD. In addition, participants with cSVD more often had nocturnal hypertension (12 [60.0%] vs. 16 [32.0%], P = 0.031) that was independently associated with cSVD (odds ratio 4.09 [95% CI 1.27–13.2], P = 0.019) after adjustment for age, antihypertensive medication, and ABPM quality. The same was true for masked hypertension (10 [50.0%] vs. 12 [25.0%], P = 0.030, and odds ratio 3.74 [95% CI 1.17–12.0], P = 0.020). No association was seen for elevated office BP, diurnal BP, or 24-h BP (data not shown).
Comparison of individuals with versus without cSVD
| . | Small-vessel disease . | No small-vessel disease . | P* . |
|---|---|---|---|
| n | 20 | 53 | |
| Male, n (%) | 10 (50.0) | 30 (56.6) | 0.613† |
| Age, years | 42.2 (39.3–46.2) | 39.6 (33.4–45.2) | 0.113† |
| Diabetes duration, years | 20.9 (19.2–32.1) | 21.2 (19.9–23.9) | 0.748† |
| Diabetes manifestation age, years | 19.9 (10.7–24.1) | 15.5 (11.0–22.8) | 0.638† |
| HbA1c, % [mmol/mol] | 8.2 (7.5–8.7) [66 (59–72)] | 8.0 (7.4–8.7) [64 (57–72)] | 0.647† |
| eGFR, mL/min/1.73 m2 | 106 (95–115) | 111 (104–117) | 0.122† |
| BMI, kg/m2 | 26.6 (24.6–28.5) | 27.1 (24.7–30.4) | 0.421† |
| Current smoker, n (%) | 0 (0.0) | 1 (1.9) | >0.999† |
| Microvascular complications, n (%) | 4 (20.0) | 11 (20.8) | >0.999† |
| Macrovascular complications, n (%) | 0 (0.0) | 0 (0.0) | — |
| Total cholesterol, mmol/L | 4.1 (3.7–4.8) | 4.4 (4.0–5.0) | 0.104† |
| LDL cholesterol, mmol/L | 2.1 (1.4–2.6) | 2.3 (2.1–3.0) | 0.067† |
| HDL cholesterol, mmol/L | 1.5 (1.3–1.9) | 1.5 (1.2–1.8) | 0.603† |
| Triglycerides, mmol/L | 0.9 (0.7–1.5) | 0.9 (0.7–1.3) | 0.946† |
| Lipid-lowering medication, n (%) | 6 (30.0) | 12 (22.6) | 0.551† |
| Antithrombotic medication, n (%) | 2 (10.0) | 4 (7.5) | 0.528† |
| Antihypertensive medication, n (%) | 8 (40.0) | 21 (39.6) | 0.792‡ |
| Office SBP, mmHg | 133 (124–139) | 130 (123–142) | 0.270 |
| Office DBP, mmHg | 79 (83–75) | 81 (74–85) | 0.503 |
| Office pulse, bpm | 69 ± 12 | 69 ± 12 | 0.778 |
| 24-h SBP, mmHg | 127 (124–135) | 122 (118–129) | 0.078 |
| Diurnal SBP, mmHg | 130 (127–140) | 127 (122–132) | 0.173 |
| Nocturnal SBP, mmHg | 117 (111–124) | 110 (107–116) | 0.010 |
| 24-h DBP, mmHg | 79 (76–86) | 79 (76–83) | 0.356 |
| Diurnal DBP, mmHg | 82 (79–89) | 82 (79–87) | 0.648 |
| Nocturnal DBP, mmHg | 72 (68–76) | 67 (64–72) | 0.009 |
| Nocturnal dip, % | 11 (6–15) | 13 (9–17) | 0.050 |
| 24-h pulse, bpm | 73 (68–82) | 72 (66–79) | 0.509 |
| Diurnal pulse, bpm | 76 (70–86) | 75 (70–84) | 0.552 |
| Nocturnal pulse, bpm | 63 (58–68) | 62 (56–68) | 0.658 |
| 24-h MAP, mmHg | 95 (90–101) | 94 (90–98) | 0.416 |
| Diurnal MAP, mmHg | 97 (93–104) | 97 (93–102) | 0.852 |
| Nocturnal MAP, mmHg | 86 (83–92) | 81 (78–86) | 0.006 |
| 24-h PP, mmHg | 47 (44–52) | 44 (41–48) | 0.074 |
| Diurnal PP, mmHg | 47 (45–53) | 44 (41–48) | 0.091 |
| Nocturnal PP, mmHg | 45 (41–49) | 44 (40–47) | 0.176 |
| 24-h SBP ARV, mmHg | 10 ± 3 | 10 ± 3 | 0.604 |
| 24-h DBP ARV, mmHg | 8 (7–9) | 7 (6–9) | 0.351 |
| . | Small-vessel disease . | No small-vessel disease . | P* . |
|---|---|---|---|
| n | 20 | 53 | |
| Male, n (%) | 10 (50.0) | 30 (56.6) | 0.613† |
| Age, years | 42.2 (39.3–46.2) | 39.6 (33.4–45.2) | 0.113† |
| Diabetes duration, years | 20.9 (19.2–32.1) | 21.2 (19.9–23.9) | 0.748† |
| Diabetes manifestation age, years | 19.9 (10.7–24.1) | 15.5 (11.0–22.8) | 0.638† |
| HbA1c, % [mmol/mol] | 8.2 (7.5–8.7) [66 (59–72)] | 8.0 (7.4–8.7) [64 (57–72)] | 0.647† |
| eGFR, mL/min/1.73 m2 | 106 (95–115) | 111 (104–117) | 0.122† |
| BMI, kg/m2 | 26.6 (24.6–28.5) | 27.1 (24.7–30.4) | 0.421† |
| Current smoker, n (%) | 0 (0.0) | 1 (1.9) | >0.999† |
| Microvascular complications, n (%) | 4 (20.0) | 11 (20.8) | >0.999† |
| Macrovascular complications, n (%) | 0 (0.0) | 0 (0.0) | — |
| Total cholesterol, mmol/L | 4.1 (3.7–4.8) | 4.4 (4.0–5.0) | 0.104† |
| LDL cholesterol, mmol/L | 2.1 (1.4–2.6) | 2.3 (2.1–3.0) | 0.067† |
| HDL cholesterol, mmol/L | 1.5 (1.3–1.9) | 1.5 (1.2–1.8) | 0.603† |
| Triglycerides, mmol/L | 0.9 (0.7–1.5) | 0.9 (0.7–1.3) | 0.946† |
| Lipid-lowering medication, n (%) | 6 (30.0) | 12 (22.6) | 0.551† |
| Antithrombotic medication, n (%) | 2 (10.0) | 4 (7.5) | 0.528† |
| Antihypertensive medication, n (%) | 8 (40.0) | 21 (39.6) | 0.792‡ |
| Office SBP, mmHg | 133 (124–139) | 130 (123–142) | 0.270 |
| Office DBP, mmHg | 79 (83–75) | 81 (74–85) | 0.503 |
| Office pulse, bpm | 69 ± 12 | 69 ± 12 | 0.778 |
| 24-h SBP, mmHg | 127 (124–135) | 122 (118–129) | 0.078 |
| Diurnal SBP, mmHg | 130 (127–140) | 127 (122–132) | 0.173 |
| Nocturnal SBP, mmHg | 117 (111–124) | 110 (107–116) | 0.010 |
| 24-h DBP, mmHg | 79 (76–86) | 79 (76–83) | 0.356 |
| Diurnal DBP, mmHg | 82 (79–89) | 82 (79–87) | 0.648 |
| Nocturnal DBP, mmHg | 72 (68–76) | 67 (64–72) | 0.009 |
| Nocturnal dip, % | 11 (6–15) | 13 (9–17) | 0.050 |
| 24-h pulse, bpm | 73 (68–82) | 72 (66–79) | 0.509 |
| Diurnal pulse, bpm | 76 (70–86) | 75 (70–84) | 0.552 |
| Nocturnal pulse, bpm | 63 (58–68) | 62 (56–68) | 0.658 |
| 24-h MAP, mmHg | 95 (90–101) | 94 (90–98) | 0.416 |
| Diurnal MAP, mmHg | 97 (93–104) | 97 (93–102) | 0.852 |
| Nocturnal MAP, mmHg | 86 (83–92) | 81 (78–86) | 0.006 |
| 24-h PP, mmHg | 47 (44–52) | 44 (41–48) | 0.074 |
| Diurnal PP, mmHg | 47 (45–53) | 44 (41–48) | 0.091 |
| Nocturnal PP, mmHg | 45 (41–49) | 44 (40–47) | 0.176 |
| 24-h SBP ARV, mmHg | 10 ± 3 | 10 ± 3 | 0.604 |
| 24-h DBP ARV, mmHg | 8 (7–9) | 7 (6–9) | 0.351 |
Data are mean ± SD or median (interquartile range) unless otherwise indicated. Microvascular complications: albuminuria or retinal photocoagulation. Antithrombotic medication: aspirin or warfarin. Estimated glomerular filtration rate (eGFR): Chronic Kidney Disease Epidemiology Collaboration formula. ARV, average real variability; DBP, diastolic BP; MAP, mean arterial pressure; SBP, systolic BP.
Adjusted for age, antihypertensive medication, and ABPM quality.
Unadjusted P.
Adjusted for age and quality only.
Our findings were more prominent in participants on antihypertensive therapy, among whom participants with cSVD had higher systolic BP (median 127 mmHg [interquartile range 119–132] vs. 113 mmHg [108–117], P = 0.001), higher diastolic BP (75 mmHg [70–78] vs. 67 mmHg [64–73], P = 0.021), and a higher prevalence of nocturnal and masked hypertension (7 [78.5%] vs. 7 [35.0%], P = 0.033, and 6 [75.0%] vs. 5 [23.8%], P = 0.028, respectively). In participants without antihypertensive medication, BP did not differ between those with or without cSVD.
This study indicates a link between nocturnal BP and asymptomatic microvascular disease of the brain in type 1 diabetes. As novel findings, we show that higher nocturnal systolic and diastolic BP and mean arterial pressure, as well as nocturnal and masked hypertension, are associated with cSVD in type 1 diabetes. To this date, this is the only existing study on ABPM and brain MRI in type 1 diabetes.
In healthy elderly people, an association between increased ABPM and cSVD has previously been observed (4). In accordance with our results, this study showed an association between higher nocturnal BP and cSVD and, furthermore, that elevated diurnal and 24-h BP were associated with cSVD. These discrepancies could be due to the difference in age, BP levels, or use of antihypertensive medication between the study cohorts. Nocturnal BP is, however, recognized as a stronger predictor of cardiovascular events than diurnal BP (3). Our results indicate that elevated nocturnal BP is associated with early markers of cerebrovascular disease.
We observed no association between cSVD and PP, a marker of arterial stiffness. In type 1 diabetes, arterial stiffness has been associated with cerebral white matter hyperintensities, a marker of cSVD (5). In our younger cohort, white matter hyperintensities were too infrequent for any further subanalyses. The different manifestations of cSVD (2) could potentially have different pathophysiology and, thus, also differ in their association with BP.
We observed more prominent findings in individuals on antihypertensive medication. No association was, however, found between cSVD and antihypertensive medication—as opposed to earlier observations (4). This may indicate that a higher nocturnal BP is a marker of a preexisting generalized circulatory dysregulation, or it may be due to taking BP-lowering medication during daytime.
The study limitations include the lack of power to detect more subtle differences between the groups and the cross-sectional design that limits the interpretation of causality. Nonetheless, the strengths of our study are the well-characterized study population and the detailed evaluation of both BP and cSVD.
Our findings show that cSVD in type 1 diabetes is associated with nocturnal BP and masked hypertension. Whether the link is causal or simply reflects vasculopathy and/or BP dysregulation needs further investigation.
J.M. and L.M.T. contributed equally to this work.
Article Information
Acknowledgments. The authors acknowledge the skilled technical assistance of Anna Sandelin, Jaana Tuomikangas, and Mira Korolainen. The authors also thank Pentti Pölönen, Department of Radiology, Helsinki University Hospital, for performing the MRI scans. The authors are indebted to Markku Kaste, Department of Neurology, and Dr. Oili Salonen, Department of Radiology, Helsinki University Hospital, for help in the initiation of the study.
Funding. The study was supported by grants from Folkhälsan Research Foundation, Academy of Finland (275614, 316664, and UAK10121MRI), Wilhelm and Else Stockmann Foundation, Liv och Hälsa Society, Novo Nordisk Foundation (NNF OC0013659), Sigrid Juselius Foundation, Medical Society of Finland, Päivikki and Sakari Sohlberg Foundation, Finnish Foundation for Cardiovascular Research, EVO governmental grants, University of Helsinki, Diabetes Research Foundation, Diabetes Wellness Finland, Finnish Medical Foundation, Perklén Foundation, Eye Foundation in Finland, and Eye and Tissue Bank Foundation.
None of funding bodies had any role in the study design, collection, analysis, or interpretation of data or any role in the writing of the manuscript or the decision to submit the manuscript for publication.
Duality of Interest. M.I.E. is a shareholder of BCB Medical Oy. D.G. has received lecture or advisory honoraria from AstraZeneca, Boehringer Ingelheim, Fresenius, GE Healthcare, and Novo Nordisk and support to attend medical meetings from CVRx and Sanofi. P.S. has received lecture honoraria from Bayer and Santen Pharmaceutical. T.T. is an advisory board member of Boehringer Ingelheim. P.‐H.G. is an advisory board member of AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Medscape, Merck Sharp & Dohme (MSD), Mundipharma, Novartis, Novo Nordisk, and Sanofi and has received lecture honoraria from Astellas, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Elo Water, Genzyme, Janssen, Medscape, MSD, Mundipharma, Novartis, Novo Nordisk, PeerVoice, Sanofi, and SCIARC. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. M.I.E., D.G., S.S., C.F., P.S., R.L., T.T., J.P., P.-H.G., J.M., and L.M.T. contributed to the study design and acquisition of data, as well as the interpretation of data. M.I.E. and L.M.T. had the main responsibility for analyzing the data and writing the first draft of the manuscript. D.G., S.S., C.F., P.S., R.L., T.T., J.P., P.-H.G., and J.M. critically revised the manuscript. P.-H.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the 54th Annual Meeting of the Scandinavian Society for the Study of Diabetes, Stockholm, Sweden, 10–12 April 2019, and at the 55th Annual Meeting of the European Association for the Study of Diabetes, Barcelona, Spain, 16–20 September 2019.
