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ADA/JDRF Type 1 Diabetes Sourcebook, Excerpt #13: Setting Treatment Targets, Part 2 of 2

Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor

ADA-JDRF-Type-1-Diabetes-Sourcebook-image

Jane Lee Chiang, MD, and Stephen E. Gitelman, MD
GUIDELINES

Current guidelines for glycemic control from select organizations worldwide are shown in Table 6.4.19-22,62 Due to the special nature of T1D, only those guidelines that are intended for T1D or that specify self-monitored blood glucose targets are included. In general, guidelines reflect glucose targets established by the DCCT. However, all guidelines recommend that targets be individualized based upon life expectancy and risk for severe hypoglycemia. Conversely, most guidelines allow lower targets for those in which it can be achieved safely, but as noted above, most patients with T1D have difficulty reaching current targets….

Interpretation of Guidelines

A1C (see Table 6.4). The current guidelines for A1C reflect the balance between the continuous benefits achieved by lowering A1C with the increased risk of hypoglycemia as A1C declines (Table 6.4).19–22,63 As the A1C falls, the hypoglycemia risk increases exponentially.1 However, since many people with T1D live beyond the duration of time captured in the DCCT, even a small increase in A1C will likely have cumulative adverse effects over time. Based upon evidence from the DCCT, an A1C <7% still appears reasonable for most. However, in select patients for whom it can be done safely, a lower target should be considered. Indeed, as technologies such as continuous glucose monitoring and closed-loop insulin pumps evolve, lower glucose targets may be achievable without increasing the risk of severe hypoglycemia. Such interventions, if successfully established, would warrant a reappraisal of the target A1C.

Glucose (see Table 6.4). Because most patients with T1D are treated with complex insulin regimens, actual insulin titration relies more upon frequent self-monitored or continuous glucose profiles than it does on A1C. Targets by various organizations generally reflect those used by the DCCT (Table 6.4).19-22,63 Post-meal targets should be considered, particularly in those patients not meeting A1C targets. Although some normative data exist for continuous glucose monitoring, there are no long-term outcomes studies to warrant the reestablishment of separate targets.64

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Glycemic Variability. A measure of glycemic variability, such as SD, should be considered to guide interventions aimed at preventing severe hypoglycemia, since such episodes are preceded by periods of increased glycemic variability.65,66 This is of particular relevance in patients with prior episodes of severe hypoglycemia or with hypoglycemia unawareness. There are currently few data to support the use of one measure over another. However, SD is readily available from downloaded reports of many insulin pumps and glucose meters. Since SD is directly proportional to mean glucose (MG), it must be reported as a percent-age of mean glucose, known as the coefficient of variation (%CV). One simple approach proposes that the optimal MG/SD value should be <3, whereas a value >2 is proposed as poor.63 Further data are needed to determine whether these cut-offs are the best predictors of outcomes such as severe hypoglycemia. CGM data show that the cutoff for the interquartile range for %CV among patients with diabetes is 33.5–40.6%.67 Glycemic variability should be assessed using continuous glucose monitoring or frequent glucose measurements (minimum of every 4 h) for optimal use.68

Alternative markers. Where there are known conditions that affect the accuracy of A1C or where A1C and self-monitored blood glucoses are discrepant, alternative markers of glycemia, such as fructosamine, glycoalbumin, or 1,5-anhydroglucitol, could be considered.19 While there are insufficient data to warrant the establishment of a specific target level for alternative markers of glycemia, these markers can be used to track patients over time.69 These markers have not been studied adequately as predictors of long-term complications and it is unclear whether interventions utilizing these markers will improve outcomes over time.

Special Considerations

Severe hypoglycemia. Higher targets are reasonable in patients with severe hypoglycemia or hypoglycemia unawareness in order to restore hypoglycemia sensitivity.70 In these cases, a higher target A1C may be reasonable, but relaxed example, instead of a premeal target of 70–130 mg/dl, the premeal target would be 90–180 mg/dl. Ultimately, the degree of relaxation of glucose targets is that which eliminates hypoglycemia without causing severe hyperglycemia or ketoacidosis. Relaxation of glycemic targets for only a short period of time may restore hypoglycemia awareness, which may allow for resumption of somewhat tighter targets.

Limited life expectancy/cognitive limitations. We advise higher targets for patients with limited life expectancy and patients with cognitive limitations in which tighter glucose targets are not considered feasible or safe. These targets must be individualized for each patient and their circumstances.

Pregnancy (see Table 6.5). Targets for pregnancy are mainly derived from large randomized controlled trials of women with gestational diabetes (Table 6.5).19,22,71–72 However, some data from T1D are available. In pregnancy, women with T1D maintained with meal glucose <95 mg/dl in the second and third trimesters minimize the risk of fetal macrosomia.73 A CGM study determined that early-onset large-for-gestational-age is associated with hyperglycemia in all three trimesters.74 In another cohort study of 289 patients with T1D, A1C <7% was present in 84% but macrosomia still occurred in nearly half of pregnancies.75 A1C was a significant predictor but only explained 5% of the variance in macrosomia. This is believed to be due to a greater importance of postprandial hyperglycemia.76,77,78 In addition, suboptimal glycemic control (A1C >8.0% early pregnancy, >6.1% at 26 weeks, or >7.0% at 34 weeks) was associated with increased risk of preeclampsia.79 A randomized controlled trial demonstrated that postprandial glucose targeting reduced this risk.72 Finally, suboptimal first trimester median blood glucose >120 mg/dl80 and A1C >7%81 were associated with increased risk of congenital malformations and abortions. Both ACOG75 and ADA19 have published guidelines for specific glucose targets as well as other countries.22,76–78 Most guidelines recommend fasting glucose in the <100 mg/dl range and postprandial glucose <140 mg/dl as well as an A1C as close to 6.0% as possible during pregnancy, if it can be done without severe hypoglycemia. (See chapter 17.)

Hospitalized patients (see Table 6.6). There are no guidelines that specifically address glucose targets for patients with T1D in the hospital. Most of these recommendations are based upon extrapolation from randomized controlled trials of predominantly patients with stress hyperglycemia or T2D (Table 6.6).82

The current American Diabetes Association/American Association of Clinical Endocrinology hospital guidelines recommend a target glucose of 140–180 mg/dl in the ICU for most patients, with targets of 110–140 possible for selected patients if it can be safely attained. In non-ICU settings, recommendations are for fasting glucose <140 mg/dl and random glucose <180 mg/dl until further data are available.83 The Endocrine Society published recommendations for meal-specific targets for non–critical care settings, including a fasting glucose <140 mg/dl and postprandial target of <180 mg/dl,84 while the American College of Physicians allowed a higher range of 140–200 mg/dl.85 These targets are generally higher than that advocated for most outpatients with diabetes. The recommendations are based largely upon the NICE-SUGAR study (both T1D and T2D patients), which showed that tight glycemic control (target glucose 80–110 mg/dl) compared to standard care (target glucose 140– 180 mg/dl) resulted in DCMS158CG2

higher frequency of severe hypoglycemia and mortality in the intensively treated group.86 However, NICE-SUGAR did not address whether glycemic control targeting a more modest glucose range (110–140 mg/dl) is better. As a result, the guidelines suggest that an intermediate target glucose range between 110–140 mg/dl may be reasonable in certain populations (for example, postcardiac surgery) and institutions and patients where it can be done safely. In children, higher targets may be advised in the hospital.87 Improvements in technology, such as more precise methods of glucose monitoring and computerized (or even closed-loop) intravenous infusion algorithms are ultimately needed to determine whether achievement of normoglycemia is beneficial.87,88

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Blood Pressure

Current trends. In the DCCT, 44% of patients developed incident hypertension during the 15-year follow-up, for which hyperglycemia was a major risk factor of CV events.89 Thus, hypertension is felt to be a consequence rather than a cause of nephropathy. However, patients were excluded from the DCCT if they had hypertension (defined as >140/90 mmHg) at entry. In the EDC and EURO-DIAB studies, the prevalence of treatment for hypertension was 7–10% (mean diabetes duration 14–19 years).48 In a large Swedish study of patients with T1D there was a slow improvement in blood pressure and cholesterol over time, but only 61% of patients achieved a mean blood pressure <130/80 mmHg.37 Other studies demonstrate that hypertension is suboptimally managed in patients with T1D, although this has improved over time.90,91

Association with complications. Diabetes significantly increases the prevalence of CVD, with T1D conferring an independent risk factor for premature morbidity and mortality related to its duration, control, and association with traditional CV risk factors including hypertension and hyperlipidemia.48,92

Blood pressure management was not a salient feature of the DCCT. In the UKPDS (which enrolled patients with T2D), a 10 mmHg increase in systolic blood pressure was associated with an 11% rise in myocardial infarction, a 13% rise in microvascular disease, and a 15% rise in diabetes-related mortality.93 Numerous other large trials, including the HOT trial, HOPE, LIFE, and ALLHAT studies have also shown significant improvement in CV outcomes and slowed progression of microvascular complications when aggressive blood pressure targets are achieved, albeit largely in individuals with T2D.94,95,96,97 Achievement of tighter control to <130 mmHg systolic that was examined in 6,400 patients with diabetes and CVD in the International Verapamil/Trandolapril Study (INVEST) did not reveal further improvement of CV outcomes compared with the usual 130–140 mmHg, but patients were not randomized to different targets.98 Nor was randomization to tighter blood pressure control (systolic <120 mmHg) found to be beneficial on the primary outcome in patients with T2D in the ACCORD study, although there was a statistically significant reduction in strokes, a secondary outcome.99

Guidelines. On the basis of these findings, although not specifically conducted for T1D, ADA guidelines recommend a blood pressure target of <130/80.19 The NICE guidelines recommend intervention at 135/85 mmHg unless the individual has an abnormal albumin excretion rate or at least two of the metabolic syndrome features, in which case it should be initiated at 130/80 mmHg.20

Interpretation of guidelines. Individuals should have routine blood pressure checks at diabetes visits.19 According to the ADA, those with systolic blood pressure >130 mmHg and diastolic blood pressure >80 mmHg, despite lifestyle interventions for a maximum of 3 months, should be started on a pharmacologic agent blocking the renin angiotensin system.19 Although a systolic blood pressure of >140 mmHg clearly results in worse outcomes, further evidence is needed to support targeting a systolic blood pressure significantly <130 mmHg in T1D. Some variation may be appropriate based on individual response and tolerance to therapy as well as specific characteristics.

Special circumstances: Nephropathy. In patients who develop diabetic nephropathy characterized by persistent proteinuria, optimization of blood pressure can slow the progression of renal damage. The blood pressure targets are the same for individuals with T1D with or without nephropathy per ADA,19 AACE,63 NICE,20 and Canadian22 guidelines. The Australian guidelines, however, conclude a blood pressure target <125/75 mmHg in the presence of 1 g daily or more of proteinuria.21 In addition to controlling blood pressure, ACE inhibitor therapy has decreased albuminuria and prevented worsening nephropathy while ARBs have reduced proteinuria. These renal-protective effects were demonstrated in a study of 698 microalbuminuric patients without hypertension.100 Those receiving ACE inhibitors had a reduction in progression to macroalbuminuria and an increase in regression to nonalbuminuria.101

Special circumstances: Pregnancy. In pregnant women with T1D, hypertension is more commonly associated with preeclampsia and complicates the pregnancy 40–45% of the time.102 Hypertension may result in very adverse outcomes, and thus the blood pressure target throughout the pregnancy is lower, at 110–129/65–79 mmHg, to protect maternal health and fetal growth.76 ACE inhibitors and ARBs are contraindicated during pregnancy given associated risk of increased congenital malformations. Instead, calcium channel blockers, β blockers, hydralazine, and methyldopa should be used to achieve blood pressure target goal.103 (Also see chapter 17.)

Low Density Lipoprotein Cholesterol

Current trends. While T2D most commonly presents with hypertriglyceridemia, low HDLc, and increased LDLc,104 in T1D, lipid and lipoprotein concentrations may be normal but present with impaired function and increased atherogenicity due to oxidation and glycation of lipoproteins.105,106,107 In a large Swedish national registry study, only 48% of patients receiving lipid lowering agents achieved the goal LDLc of <100 mg/dl.37 Suboptimal control has also been reported in the U.S., with only 5.5% meeting targets, particularly children.48

Association with complications. Dyslipidemia is highly prevalent in people with diabetes, further increasing the risk of microvascular complications as seen in DCCT/EDIC108 along with CVD and associated mortality. Overall, in T1D evidence indicates an effect of statin on lipids consistent with the general population. The Heart Protection Study (HPS) is one of a few studies that examined the effect of a statin in patients with T1D, and nearly 600 patients were included. The HPS found a CV risk reduction similar to that of patients with T2D.109 This study supported the reduction of baseline LDLc level by about 30–40% as an alternative therapeutic goal. A large meta-analysis of statin trials demonstrated similar CV risk reduction in patients with T1D (1,566 patients) compared to patients with T2D and patients without diabetes.110

Guidelines. According to the ADA and the National Cholesterol Education Program’s Adult Treatment Panel III, the primary goal for individuals without overt CVD is an LDL <100 mg/dl and <70 mg/dl with overt CVD or more than two major CV risk factors.19,111 However, statins should be started in individuals over the age of 40 years or with CV risk factors or overt disease, regardless of baseline lipid levels.19 The Adult Treatment Panel III guidelines were last updated in 2002 and an updated version is expected to be released soon.112 The target HDLc is >40 mg/ dl for men and >50 mg/dl for women, while that for triglycerides is <150 mg/dl.19

Interpretation of guidelines. To screen adult patients for dyslipidemia, a fasting lipid profile should be checked at least annually, and then repeated every 1–2 years. To achieve target goals for lipid measures, aggressive lifestyle and medical management of dyslipidemia is necessary.

SPECIAL CIRCUMSTANCES
Pregnancy

Statins are contraindicated during pregnancy (category X) and should be stopped prior to conception.113 Thus, adequate patient education and family planning counseling are necessary for women with T1D of childbearing age.

Other Lipid Targets

Additional measures of atherogenic lipid lipoproteins have been explored. The TC/HDLc ratio (or non-HDL cholesterol) has been proposed as a specific index of CV risk and a secondary goal of therapy to <4.0 (for the ratio) or 30 mg/dl above the LDLc target for non-HDLc) is suggested.19,114 The use of apo B to predict CVD events with target of <80 mg/dl in patients with CVD and <90 mg/dl in those without has been recommended by some,115 but inadequate supporting evidence exists.

Other Metabolic Variables

Intensive glycemic control was associated with greater weight gain and risk of metabolic syndrome compared to the standard group in the DCCT.116 However, the benefits of glycemic control appear to mitigate any observed increase in risk of complications. In contrast, insulin resistance at baseline (assessed with estimated glucose disposal rate) but not metabolic syndrome or insulin dose predicted the onset of both microvascular and macrovascular complications. In another study within the DCCT, waist circumference was associated with increased risk of incident microalbuminuria but not decline in creatinine clearance.117 However, those patients in the intensive group who did not gain weight still experienced a survival benefit and lower risk of complications compared to those who gained weight.118

In EURODIAB, waist-to-hip ratio and triglycerides (as markers of insulin resistance) were independent predictors of incident retinopathy.119 Furthermore, waist-to-hip ratio and triglycerides were nearly as strong as albumin excretion rate for predicting microalbuminuria.120 Increased weight was a predictor of progression from microalbuminuria to macroalbuminuria.51

As noted above, dyslipidemia commonly associated with metabolic syndrome or T2D may be observed in patients with T1D. If low HDLc results in a persistently elevated ratio, niacin therapy may be added to statin. Niacin combined with statin was associated with >13% absolute risk reduction for CV outcomes in the HATS nondiabetic cohort.121 However, CV risk reduction was not confirmed in a large prospective study of patients with T2D who were already receiving statin therapy, and there was suggestion of increased risk of stroke.122 Fibrate therapy is recommended for individuals with significantly elevated triglyceride levels although it revealed no reduction in CV outcomes in a large trial of T2D patients unless there was dyslipidemia present at baseline.19,123 Outside of lowering triglycerides to prevent pancreatitis, further research is needed to determine the optimal role of managing dyslipidemia beyond statin therapy in patients with T1D.

FUTURE CLINICAL RESEARCH: FILLING THE GAPS

There are many unanswered questions surrounding optimal targets for risk factors of microvascular and macrovascular complications. The following is a list of more urgent questions.

Pediatrics
Glucose

■ Effects of severe hypoglycemia on cognitive function in children with T1D stratified by age in order to more closely establish any threshold effect Blood pressure

■ Optimal blood pressure targets and long-term safety and efficacy of blockade of the  renin-angiotensin system LDLc

■ Optimal targets and long-term safety and efficacy of statins

Adults Glucose

■ Updated risk of complications and hypoglycemia risk at various A1C strata and duration of diabetes

■ Assessment of the long-term risk of complications using continuous glucose monitoring data, including glucose area under the curve, time spent in hyperglycemic and hypoglycemic ranges, and measures of glycemic variability

■ Robust longitudinal assessment of the prevalence of severe hypoglycemia in relationship to newer technologies, such as insulin analogues, continuous subcutaneous insulin infusion, and continuous glucose monitoring

■ Optimal targets for avoidance of hypoglycemia in hypoglycemia-associated autonomic failure

■ Utility and comparison of measures of glycemic variability for preventing severe hypoglycemia

■ Utility of alternative markers of glycemia for predicting long-term complications

Blood pressure

■ Further characterization of the relative role of blood pressure in the development of microvascular and macrovascular complications

■ Optimal target blood pressure in patients by duration of diabetes (with separate attention to essential hypertension and that presumably mediated by early nephropathy)

■ Optimal blood pressure targets in nephropathy

LDLc

■ Optimal LDLc level for CV prevention in patients with T1D by age and duration of diabetes

■ Prospective studies further characterizing the role of lipids in the development of microvascular complications

■ Longitudinal studies assessing and comparing the association between various components of the lipid profile, including lipoprotein analysis on risk of CVD in patients with T1D

■ Investigation of any additive benefit of managing dyslipidemia associated with metabolic syndrome

CONCLUSION

It is clear that the optimal targets for T2D cannot always be extrapolated to patients with T1D, since the pathophysiology, disease course, and management differ so markedly. In patients with T1D, it is likely that glycemic control is even more important than for T2D, although other factors such as blood pressure and lipids play a key role. Targets should include A1C, but A1C alone has little utility for making specific adjustments in glucose-lowering therapy. Instead targets should include goals for glucose in a variety of circumstances, such as fasting, premeal and postmeal, and possibly for glycemic variability. In general, targets must be individualized to fit the specific circumstances of the patient, taking into account the risks and benefits of the intervention, particularly in the case of glucose targets. Newer technologies may allow tighter targets over time without increasing the risk of hypoglycemia. Therefore, targets should be frequently reevaluated among individuals and among the population as a whole.

REFERENCES

1. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993

2. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Had-den D, Turner RC, Holman RR: Association of glycaemia with macrovas-cular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405– 1412, 2000

3. Fox CS, Larson MG, Leip EP, Meigs JB, Wilson PW, Levy D: Glycemic status and development of kidney disease: the Framingham Heart Study. Diabetes Care 28:2436–2440, 2005

4. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J, Brancati FL: Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 362:800–811, 2010

5. Taubert G, Winkelmann BR, Schleiffer T, März W, Winkler R, Gök R, Klein B, Schneider S, Boehm BO: Prevalence, predictors, and consequences of unrecognized diabetes mellitus in 3266 patients scheduled for coronary angiography. Am Heart J 145:285–291, 2003

6. Juutilainen A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M: Similarity of the impact of type 1 and type 2 diabetes on cardiovascular mortality in middle-aged subjects. Diabetes Care 31:714–719, 2008

7. Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP: DARTS/MEMO Collaboration: Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. Diabet Med 22:749–755, 2005

8. Kuenen JC, Borg R, Kuik DJ, Zheng H, Schoenfeld D, Diamant M, Nathan DM, Heine RJ: ADAG Study Group: Does glucose variability influence the relationship between mean plasma glucose and HbA1c levels in type 1 and type 2 diabetic patients? Diabetes Care 34:1843–1847, 2011

9. Greven WL, Beulens JW, Biesma DH, Faiz S, de Valk HW: Glycemic vari-ability in inadequately controlled type 1 diabetes and type 2 diabetes on intensive insulin therapy: a cross-sectional, observational study. Diabetes Technol Ther 12:695–699, 2010

10. Lawrie SM, Whalley H, Kestelman JN, Abukmeil SS, Byrne M, Hodges A, Rimmington JE, Best JJ, Owens DG, Johnstone EC: Magnetic resonance imaging of brain in people at high risk of developing schizophrenia. Lancet 353:30–33, 1999

11. Perantie DC, Lim A, Wu J, Weaver P, Warren SL, Sadler M, White NH, Hershey T: Effects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Pediatr Diabetes 9:87–95, 2008

12. Patiño-Fernández AM, Delamater AM, Applegate EB, Brady E, Eidson M, Nemery R, Gonzalez-Mendoza L, Richton S: Neurocognitive function-ing in preschool-age children with type 1 diabetes mellitus. Pediatr Diabetes11:424–430, 2010

13. Gaudieri PA, Chen R, Greer TF, Holmes CS: Cognitive function in chil-dren with type 1 diabetes: a meta-analysis.Diabetes Care 31(9):1892–1897, 2008

14. Northam EA, Rankins D, Lin A, Wellard RM, Pell GS, Finch SJ, Werther GA, Cameron FJ: Central nervous system function in youth with type 1 diabetes 12 years after disease onset. Diabetes Care 32:445–450, 2009

15. Asvold BO, Sand T, Hestad K, Bjørgaas MR: Cognitive function in type 1 diabetic adults with early exposure to severe hypoglycemia: a 16-year fol-low-up study. Diabetes Care 33:1945–1947, 2010

16. Jacobson AM, Musen G, Ryan CM, Silvers N, Cleary P, Waberski B, Bur-wood A, Weinger K, Bayless M, Dahms W, Harth J: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 356:1842–1852, 2007

17. Musen G, Jacobson AM, Ryan CM, Cleary PA, Waberski BH, Weinger K, Dahms W, Bayless M, Silvers N, Harth J, White N: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Impact of diabetes and its treatment on cognitive function among adolescents who participated in the Diabetes Control and Complications Trial. Diabetes Care 31:1933–1938, 2008

18. Sima AAF: Encephalopathies: the emerging diabetic complications. Acta Diabetol 47:279–293, 2010

19. American Diabetes Association: Standards of medical care in diabetes: 2012. Diabetes Care 35 (Suppl. 1):S11–S63, 2012

20. Rewers M, Pihoker C, Donaghue K, Hanas R, Swift P, Klingensmith GJ: Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes 10 (Suppl. 12):71–81, 2009

21. Chemtob CM, Hochhauser CJ, Shemesh E, Schmeidler J, Rapaport R: Does poor early metabolic control predict subsequent poor control in young chil-dren with type 1 diabetes: an exploratory study. J Diabetes 3:153–157, 2011

22. Shalitin S, Phillip M: Which factors predict glycemic control in children diagnosed with type 1 diabetes before 6.5 years of age? Acta Diabetol 49:355– 362, 2012 [Epub ahead of print]

23. Eppens MC, Craig ME, Cusumano J, Hing S, Chan AK, Howard NJ, Silink M, Donaghue KC: Prevalence of diabetes complications in adolescents with type 2 compared with type 1 diabetes. Diabetes Care 29:1300–1306, 2006

24. Hanas R, Donaghue KC, Klingensmith G, Swift PG: ISPAD clinical prac-tice consensus guidelines 2009 compendium. Pediatr Diabetes 10 Suppl 12: 1 –2, 2009

25. Soffer B, Zhang Z, Miller K, Vogt BA, Shahinfar S: A double-blind, placebo- controlled, dose-response study of the effectiveness and safety of lisinopril for children with hypertension. Am J Hyperten 16:795–800, 2003

26. Wells T, Frame V, Soffer B, Shaw W, Zhang Z, Herrera P, Shahinfar S: Enal-april Pediatric Hypertension Collaborative study group: A double-blind, placebo-controlled, dose-response study of the effectiveness and safety of enalapril for children with hypertension. J Clin Pharma 42: 870–880, 2002

27. Järvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimäki T, Rönnemaa T, Viikari J, Raitakari OT: Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes.Circulation 109:1750–1755, 2004

28. De Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, van Trotsenburg AS, Bakker HD, Kastelein JJ: Simvastatin in Children Study Group: Efficacy and safety of stain therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo- controlled trial with simvastatin. Circulation 106:2231–2237, 2002

29. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Büller HR, Sijbrands EJ, Kastelein JJ: Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA292:331–337, 2004

30. Dietary Intervention Study in Children (DISC): Writing Group for the DISC Collaborative Research Group: Efficacy and safety of lowering dietary intake of fat and cholesterol in children with elevated low-density lipoprotein cholesterol. JAMA 273:1429–1435, 1995

31. Beck RW, Tamborlane WV, Bergenstal RM, Miller KM, Dubose SN, Hall CA, for the T1D Exchange Clinic Network. J Clin Endocrinol Metab 20 Sep-tember 2012. [Epub ahead of print] PMID: 22996145

32. Eeg-Olofsson K, Cederholm J, Nilsson PM, Gudbjörnsdóttir S, Eliasson B: Steering Committee of the Swedish National Diabetes Register: Glycemic and risk factor control in type 1 diabetes: results from 13,612 patients in a national diabetes register. Diabetes Care 30:496–502, 2007

33. Rosenbauer J, Dost A, Karges B, Hungele A, Stahl A, Bächle C, Gerstl EM, Kastendieck C, Hofer SE, Holl RW: DPV Initiative and the German BMBF Competence Network Diabetes Mellitus: Improved metabolic control in children and adolescents with type 1 diabetes: a trend analysis using pro-spective multicenter data from Germany and Austria. Diabetes Care 35:80– 86, 2012

34. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB: Is glycemic control improv-ing in U.S. adults? Diabetes Care31:81–86, 2008

35. Chase HP, Lockspeiser T, Peery B, Shepherd M, MacKenzie T, Anderson J, Garg SK: The impact of the diabetes control and complications trial and humalog insulin on glycohemoglobin levels and severe hypoglycemia in type 1 diabetes. Diabetes Care 24:430–434, 2001

36. Nathan DM, Zinman B, Cleary PA, Backlund JY, Genuth S, Miller R, Orchard TJ: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group: Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the diabetes control and complications trial/epidemiology of diabetes interventions and complications and Pittsburgh epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 169:1307– 1316, 2009

37. Writing Team for the Diabetes Control and Complications Trial/Epidemi-ology of Diabetes Interventions and Complications Research Group: Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 287:2563–2569, 2002

38. Lachin JM, Genuth S, Nathan DM, Zinman B, Rutledge BN: DCCT/EDIC Research Group: Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial—revisited.Diabetes 57:995–1001, 2008

39. Diabetes Control and Complications Trial Research Group: The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes45:1289–1298, 1996

40. White NH, Sun W, Cleary PA, Tamborlane WV, Danis RP, Hainsworth DP, Davis MD: DCCT-EDIC Research Group: Effect of prior intensive ther-apy in type 1 diabetes on 10-year progression of retinopathy in the DCCT/ EDIC: comparison of adults and adolescents. Diabetes 59:1244–1253, 2010

41. Albers JW, Herman WH, Pop-Busui R, Feldman EL, Martin CL, Cleary PA, Waberski BH, Lachin JM: Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group: Effect of prior intensive insulin treatment during the Diabetes Con-trol and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complica-tions (EDIC) Study.Diabetes Care 33:1090–1096, 2010

42. Writing Team for the Diabetes Control and Complications Trial/Epide-miology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) Study.JAMA 290:2159– 2167, 2003

43. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005

44. Zgibor JC, Ruppert K, Orchard TJ, Soedamah-Muthu SS, Fuller J, Chaturvedi N, Roberts MS: Development of a coronary heart disease risk prediction model for type 1 diabetes: the Pittsburgh CHD in type 1 diabetes risk model.Diabetes Res Clin Pract 88:314–321, 2010

45. Prince CT, Becker DJ, Costacou T, Miller RG, Orchard TJ: Changes in glycaemic control and risk of coronary artery disease in type 1 diabetes mel-litus: findings from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC). Diabetologia 50:2280–2288, 2007

46. Vergouwe Y, Soedamah-Muthu SS, Zgibor J, Chaturvedi N, Forsblom C, Snell-Bergeon JK, Maahs DM, Groop PH, Rewers M, Orchard TJ, Fuller JH, Moons KG: Progression to microalbuminuria in type 1 diabetes: devel-opment and validation of a prediction rule. Diabetologia 53:254–262, 2010

47. Giorgino F, Laviola L, Cavallo Perin P, Solnica B, Fuller J, Chaturvedi N: Factors associated with progression to macroalbuminuria in microalbumin-uric type 1 diabetic patients: the EURODIAB Prospective Complications Study.Diabetologia 47:1020–1028, 2004

48. Rottiers R, Veglio M, Fuller JH: EURODIAB Prospective Complications Study Group: Risk factors for progression to proliferative diabetic reti-nopathy in the EURODIAB Prospective Complications Study. Diabetologia44:2203–2209, 2001

49. Soedamah-Muthu SS, Chaturvedi N, Toeller M, Ferriss B, Reboldi P, Michel G, Manes C, Fuller JH: EURODIAB Prospective Complications Study Group: Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study. Diabetes Care 27:530–537, 2004

50. Hammes HP, Kerner W, Hofer S, Kordonouri O, Raile K, Holl RW: DPV- Wiss Study Group: Diabetes retinopathy in type 1 diabetes—a contempo-rary analysis of 8,784 patients. Diabetologia 43:1977–1984, 2011

51. Diabetes Control and Complications Trial Research Group: Adverse events and their association with treatment regimens in the diabetes control and complications trial. Diabetes Care 18:1415–1427, 1995

52. Kilpatrick ES, Rigby AS, Atkin SL, Frier BM: Does severe hypoglycae-mia influence microvascular complications in type 1 diabetes? An analysis of the diabetes control and complications trial database. Diabet Med doi: 10.1111/j.1464-5491.2012.03612.x, 2012. [Epub ahead of print]

53. Cox D, Clarke W, Gonder-Frederick L, Kovatchev B: Driving mishaps and hypoglycaemia: risk and prevention.Int J Clin Pract (Suppl.)38–42, 2001

54. Gonder-Frederick LA, Zrebiec JF, Bauchowitz AU, Ritterband LM, Magee JC, Cox DJ, Clarke WL: Cognitive function is disrupted by both hypo- and hyperglycemia in school-aged children with type 1 diabetes: a field study.Diabetes Care 32:1001–1006, 2009

55. Diabetes Control and Complications Trial Research Group: The relation-ship of glycemic exposure (HbA1c) to the risk of development and progres-sion of retinopathy in the diabetes control and complications trial. Diabetes 44:968–983, 1995

56. Kilpatrick ES, Rigby AS, Atkin SL: Variability in the relationship between mean plasma glucose and HbA1c: implications for the assessment of glyce-mic control. Clin Chem 53:897–901, 2007

57. Kilpatrick ES, Rigby AS, Atkin SL: The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 29:1486–1490, 2006

58. Service FJ, O’Brien PC: The relation of glycaemia to the risk of develop-ment and progression of retinopathy in the diabetic control and complica-tions trial. Diabetologia 44:1215–1220, 2001

59. Kilpatrick ES, Rigby AS, Goode K, Atkin SL: Relating mean blood glucose and glucose variability to the risk of multiple episodes of hypoglycemia in type 1 diabetes. Diabetologia 50:2553–2561, 2007

60. Niskanen L, Virkamäki A, Hansen JB, Saukkonen T: Fasting plasma glucose variability as a marker of nocturnal hypoglycemia in diabetes: evidence from the PREDICTIVE Study. Diabetes Res Clin Pract 86:e15–e18, 2009

61. Wadén J, Forsblom C, Thorn LM, Gordin D, Saraheimo M, Groop PH: Finnish Diabetic Nephropathy Study Group: A1C variability predicts incident cardiovascular events, microalbuminuria, and overt diabetic nephropa-thy in patients with type 1 diabetes. Diabetes 58:2649–2655, 2009

62. Handelsman Y, JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA, Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB, Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovicˇ L, Lebovitz H, Levy P, Moghissi ES, Orzeck EA, Vinik AI, Wyne KL: AACE Task Force of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract 17 (Suppl. 2):1–53, 2011

63. Hirsch IB: Glycemic variability: it’s not just about A1C anymore! Diabetes Technol Ther 7:780–783, 2005

64. Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR: Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther 13:921–928, 2011

65. Breton M, Clarke W, Farhy L, Kovatchev B: A model of self-treatment behavior, glucose variability, and hypoglycemia-associated autonomic failure in type 1 diabetes. J Diabetes Sci Technol 3:331–337, 2007

66. Kovatchev BP, Cox DJ, Farhy LS, Straume M, Gonder-Frederick L, Clarke WL: Episodes of severe hypoglycemia in type 1 diabetes are preceded and followed within 48 hours by measurable disturbances in blood glucose. J Clin Endocrinol Metab 85:4287–4292, 2000

67. Rodbard D: Clinical interpretation of indices of quality of glycemic control and glycemic variability. Postgrad Med 123:107–118, 2011

68. Baghurst PA, Rodbard D, Cameron FJ: The minimum frequency of glucose measurements from which glycemic variation can be consistently assessed. J Diabetes Sci Technol 4:1382–1385, 2010

69. Foo JP, Mantzoros CS: The quest for the perfect biomarker of long-term gly-cemia: new studies, new trials and tribulations. Metabolism 60:1651–1654, 2011

70. Dagogo-Jack S, Rattarasarn C, Cryer PE: Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabe-tes 43:1426–1434, 1994

71. ACOG Committee on Practice Bulletins. ACOG Practice Bulletin. Clin-ical Management Guidelines for Obstetrician-Gynecologists. Number 60, March 2005. Pregestational diabetes mellitus. Obstet Gynecol 105:675, 2005

72. International Diabetes Federation Clinical Guidelines Taskforce. Chapter 17: Pregnancy in Global Guideline for Type 2 Diabetes. 2005. International Diabetes Federation, Brussels. Available at http://www.idf.org/webdata/ docs/GGT2D%2017%20Pregnancy.pdf. Accessed 20 March 2012

73. Mello G, Parretti E, Mecacci F, La Torre P, Cioni R, Cianciulli D, Scarselli G: What degree of maternal metabolic control in women with type 1 diabe-tes is associated with normal body size and proportions in full-term infants? Diabetes Care 23:1494, 2000

74. Kerssen A, de Valk HW, Visser GH: Increased second trimester maternal glucose levels are related to extremely large-for-gestational-age infants in women with type 1 diabetes. Diabetes Care 30:1069–1074, 2007

75. Evers IM, De Balk HW, Mol BWJ, ter Braak EW, Visser GH: Macrosomia despite good glycaemic control in type I diabetic pregnancy: results of a nationwide study in the Netherlands. Diabetologia 45:1484–1489, 2002

76. Jovanovic-Peterson L, Peterson CM, Reed GF, Metzger BE, Mills JL, Knopp RH, Aarons JH: Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. National Institute of Child Health and Human Development: Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 164:103–111, 1991

77. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK: Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 15:1251–1257, 1992

78. Manderson JG, Patterson CC, Hadden DR, Traub AI, Ennis C, McCance DR: Preprandial versus postprandial blood glucose monitoring in type 1 diabetic pregnancy: a randomized controlled clinical trial. Am J Obstet Gynecol 189:507–512, 2003

79. Holmes VA, Young IS, Patterson CC, Pearson DW, Walker JD, Maresh MJ, McCance DR: Diabetes and Pre-eclampsia Intervention Trial Study Group: Optimal glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabetes Care 34:1683, 2011

80. Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA: Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 84:515–520, 1994

81. Nielsen GL, Møller M, Sørensen HT: HbA1c in early diabetic pregnancy and pregnancy outcomes: a Danish population-based cohort study of 573 pregnancies in women with type 1 diabetes. Diabetes Care 29:2612–2616, 2006

82. Tridgell DM, Tridgell AH, Hirsch IB: Inpatient management of adults and children with type 1 diabetes. Endocrinol Metab Clin N Am 39:595–608, 2010

83. Moghissi ES, Korytkowski MT, DiNardo M, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE: American Association of Clinical Endocrinologists, American Diabetes Association: American Association of Clinical Endocrinologists and American Diabe-tes Association consensus statement on inpatient glycemic control. Diabetes Care. 32:1119–1131, 2009

84. Umpierrez GE, Hellman R, Korytkowski MT, Kosiborod M, Maynard GA, Montori VM, Seley JJ, Van den Berghe G: Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 97:16–38, 2012

85. Qaseem A, Humphrey LL, Chou R, Snow V, Shekelle P: Clinical Guidelines Committee of the American College of Physicians: Use of intensive insulin therapy for the management of glycemic control in hospitalized patients: a clinical practice guideline from the American College of Physicians. Ann Intern Med 154:260–267, 2011

86. Finfer S, Chittock DR, Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S, Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J, Robinson BG, Ronco JJ: NICE-SUGAR Study Investigators: Intensive versus conventional glucose control in critically ill patients. N Engl J Med 360:1283–1297, 2009

87. Fort A, Narsinghani U, Bowyer F: Evaluating the safety and efficacy of Glucommander, a computer-based insulin infusion method, in management of diabetic ketoacidosis in children, and comparing its clinical performance with manually titrated insulin infusion. J Pediatr Endocrinol Metab 22:119– 125, 2009

88. Hirsch IB: Intravenous bolus insulin delivery: implications for closed-loop control and hospital care. Diabetes Technol Ther 14:6–7, 2012

89. de Boer IH, Kestenbaum B, Rue TC, Steffes MW, Cleary PA, Molitch ME, Lachin JM, Weiss NS, Brunzell JD: Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group: Insulin therapy, hyperglycemia, and hyper-tension in type 1 diabetes mellitus. Arch Intern Med 168:1867–1873, 2008

90. Soedamah-Muthu SS, Colhoun HM, Abrahamian H, Chan NN, Mangili R, Reboldi GP, Fuller JH: the EURODIAB Prospective Complications Study Group: Trends in hypertension management in type 1 diabetes across Europe, 1989/1990–1997/1999. Diabetologia 45:13621371, 2002

91. Zgibor JC, Orchard TJ: Has control of hyperlipidemia and hypertension in patients with type 1 diabetes improved over time? Diabetes 50:1049, 2001

92. Laing SP, Swerdlow AJ, Slater SD, Botha JL, Burden AC, Waugh NR, Smith AW, Hill RD, Bingley PJ, Patterson CC, Qiao Z, Keen H: British Diabetic Association Cohort Study, II: Cause-specific mortality in patients with insu-lin-treated diabetes mellitus. Diabet Med 16:466–471, 1999

93. Adler AI, Stratton IM, Neil HA, Yudkin JS, Matthews DR, Cull CA, Wright AD, Turner RC, Holman RR: Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ 321:412–419, 2000

94. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood- pressure lowering and low dose aspirin in patients with hypertension: prin-cipal results of the Hypertension Optimal Treatment (HOT) randomized trial, HOT Study Group. Lancet 351:1755–1762, 1998

95. Heart Outcomes Prevention Evaluation Study Investigators: Effects of ramipril on cardiovascular and microvascular outcomes in people with dia-betes mellitus: results of the HOPE study and MICRO-Hope substudy. Lancet 355:253–259, 2000

96. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H: LIFE Study Group: Car-diovascular morbidity and mortality in the Losartan Intervention for End-point reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 359:995–1003, 2002

97. Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, Leenen FH, Louis GT, Margolis KL, Mathis DE, Moloo J, Nwachuku C, Panebianco D, Parish DC, Pressel S, Simmons DL, Thadani U: ALLHAT collaborative Research Group: Clinical outcomes in antihypertensive treat-ment of type 2 diabetes, impaired fasting glucose concentration, and nor-moglycemia: antihypertensive and lipid-lowering treatment to prevent heart attack trail (ALLHAT). Arch Intern Med 165:1401–1409, 2005

98. Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ: Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 304:61–68, 2010

99. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, Katz L, Peterson KA, Friedewald WT, Buse JB, Bigger JT, Gerstein HC, Ismail- Beigi F, ACCORD Study Group: Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 362:1575–1585, 2010

100. ACEI Trialist Group (ACE Inhibitors in Diabetic Nephropathy Trialist Group): Should all patients with type 1 diabetes mellitus and microalbu-minuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 134:370–379, 2001

101. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC: Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 329:828, 2004

102. Cundy T, Slee F, Gamble G, Neale L: Hypertensive disorders of pregnancy in women with type 1 and type 2 diabetes. Diabet Med 19:482–489, 2002

103. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ: Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, National Heart, Lung, and Blood Institute, National High Blood Pressure Education Program Coordinating Committee: Seventh report of the Joint National Committee on Prevention, Detection, Evalua-tion, and treatment of high blood pressure. Hypertension 42:1206–1252, 2003

104. Watts GF, Karpe F: Triglycerides and atherogenic dyslipidaemia: extend-ing treatment beyond statins in the high-risk cardiovascular patient. Heart 97:350–356, 2011

105. Kara C, Cetinkaya S, Sezgin N, Kinik ST: The effects of metabolic control on oxidized low-density lipoprotein antibodies in children and adolescents with type 1 diabetes mellitus. Pediatr Diabetes 9:17–22, 2008

106. Lopes-Virella MF, Baker NL, Hunt KJ, Lachin J, Nathan D, Virella G: DCCT/EDIC Research Group: Oxidized LDL immune complexes and coronary artery calcification in type 1 diabetes. Atherosclerosis 214:462–467, 2011

107. Lopes-Virella MF, Hunt KJ, Baker NL, Lachin J, Nathan DM, Virella G: Diabetes Control and Complications Trial/Epidemiology of Diabetes Inter-ventions and Complications Research Group: Levels of oxidized LDL and advanced glycation end products-modified LDL in circulating immune complexes are strongly associated with increased levels of carotid intima-media thickness and its progression in type 1 diabetes. Diabetes 60:582–589, 2011

108. Jenkins AJ, Lyons TJ, Zheng D, Otvos JD, Lackland DT, McGee D, Gar-vey WT, Klein RL: Diabetes Control and Complications Trial/Epidemiol-ogy of Diabetes Interventions and Complications (DCCT/EDIC) Research Group: Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Internat 64:817–828, 2003

109. Collins R, Armitage J, Parish S, Sleigh P, Peto R: Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 361:2005–2016, 2003

110. Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R, Armitage J, Baigent C, Cholesterol Treatment Trialists’ (CTT) Collaborators: Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 371:117–125, 2008

111. National Cholesterol Education Program (NCEP) Expert Panel on Detec-tion, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 106:3143–3421, 2002 112. Available at http://www.nhlbi.nih.gov/guidelines/cholesterol/atp4/index .htm. Accessed 8 October 2012

113. Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, Gunderson EP, Herman WH, Hoffman LD, Inturrisi M, Jovanovic LB, Kjos SI, Knopp RH, Montoro MN, Ogata ES, Paramsothy P, Reader DM, Rosenn BM, Thomas AM, Kirkman MS: Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations of care. Diabetes Care 31:1060–1079, 2008

114. Fodor JG, Frohlich JJ, Genest JJ Jr, McPherson PR: Working Group on Hypercholesterolemia and Other Dyslipidemias: Recommendations for the management of dyslipidemia and the prevention of cardiovascular disease: summary of the 2003 update. CMAJ 169:921–924, 2003

115. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum JL, American Diabetes Association, American College of Car-diology Foundation: Lipoprotein management in patients with cardiometa-bolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation. Diabetes Care 31:811–822, 2008

116. Kilpatrick ES, Rigby AS, Atkin SL: Insulin resistance, the metabolic syn-drome, and complication risk in type 1 diabetes: “double diabetes” in the Diabetes Control and Complications Trial. Diabetes Care 30:707–712, 2007

117. de Boer IH, Sibley SD, Kestenbaum B, Sampson JN, Young B, Cleary PA, Steffes MW, Weiss NS, Brunzell JD: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group: Central obesity, incident microalbuminuria, and change in creatinine clearance in the epidemiology of diabetes interventions and complications study. J Am Soc Nephrol 18:235–243, 2007

118. Palmer AJ, Roze S, Valentine WJ, Minshall ME, Lammert M, Nicklasson L, Spinas GA: Deleterious effects of increased body weight associated with intensive insulin therapy for type 1 diabetes: increased blood pressure and worsened lipid profile partially negate improvements in life expectancy. Curr Med Res Opin 20 (Suppl. 1):S67-S73, 2004

119. Chaturvedi N, Sjoelie AK, Porta M, Aldington SJ, Fuller JH, Songini M, Kohner EM: Markers of insulin resistance are strong risk factors for reti-nopathy incidence in type 1 diabetes. Diabetes Care 24:284289, 2001

120. Chaturvedi N, Bandinelli S, Mangili R, Penno G, Rottiers RE, Fuller JH: Microalbuminuria in type 1 diabetes: rates, risk factors and glycemic thresh-old. Kidney Int 60:219–227, 2001

121. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P, Frohlich J, Albers JJ: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 345:1583–1592, 2001

122. AIM-HIGH Investigators: Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 365:2255–2267, 2011

 

123. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M: FIELD Study Investi-gators: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD Study): randomized controlled trial. Lancet 366:1849–1861, 2005

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