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Glycemic control and vascular complications in type 1 diabetes mellitus

Glycemic control and vascular complications in type 1 diabetes mellitus
Authors:
Silvio E Inzucchi, MD
Beatrice Lupsa, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Sep 15, 2022.

INTRODUCTION — Morbidity from diabetes is a consequence of both macrovascular disease (atherosclerosis) and microvascular disease (retinopathy, nephropathy, and neuropathy). The importance of intensive glycemic control for protection against microvascular and macrovascular disease in diabetes was demonstrated for type 1 diabetes in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study [1,2].

Glycemic targets and the effects of glycemic control on microvascular and macrovascular complications in type 1 diabetes will be reviewed here. Glycemic control and vascular complications in type 2 diabetes is discussed separately. (See "Glycemic control and vascular complications in type 2 diabetes mellitus".)

PATHOGENESIS — The mechanism by which lack of glycemic control predisposes to vascular disease is incompletely understood. Two proposed contributing factors are advanced glycation end products and sorbitol; protein kinase C and other factors also may contribute (algorithm 1). In addition to systemic factors, organ-specific factors also appear to be important. In the kidney, for example, stimulation of mesangial matrix production by hyperglycemia, activation of protein kinase C, and an increasing degree of intraglomerular hypertension may contribute to the glomerular injury.

Genetic predisposition may be another important factor. This was illustrated in a report from the Diabetes Control and Complications Trial (DCCT) in which 372 patients and 467 first-degree relatives with diabetes were evaluated [3,4]. Severe retinopathy was three times more frequent among the relatives of patients with retinopathy than among relatives of patients who did not have retinopathy. Familial clustering was also noted for diabetic nephropathy. However, genome-wide association and candidate gene association studies generally have been unsuccessful in identifying significant replicable signals for retinopathy or nephropathy [5].

A more in-depth discussion of the pathogenesis of diabetic nephropathy, retinopathy, and neuropathy can be found elsewhere. (See "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Pathogenesis' and "Diabetic retinopathy: Pathogenesis" and "Pathogenesis of diabetic polyneuropathy", section on 'Pathophysiology'.)

GLYCEMIC TARGETS — Intensive insulin therapy should be attempted in all appropriate patients with type 1 diabetes as early in the course of disease as is safely feasible. Both patient and clinician education and support are required to perform this task safely. Intensive management has been made easier to achieve and safer through advances in the technological aspects of type 1 diabetes management. These include insulin pumps and continuous glucose monitoring (CGM), especially when linked in so-called "hybrid closed-loop" devices. (See "Continuous subcutaneous insulin infusion (insulin pump)" and "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems' and "Measurements of glycemia in diabetes mellitus", section on 'CGM to estimate average glucose'.)

In patients with type 1 diabetes, lower levels of glycemia result in decreased rates of retinopathy, nephropathy, and neuropathy as well as fatal and nonfatal cardiovascular events and mortality but an increased risk of hypoglycemia. Initiation of intensive therapy as early as possible after the diagnosis of type 1 diabetes (when there is residual beta cell function) provides the most benefit while reducing the risk of severe hypoglycemia [6]. (See 'Microvascular disease' below and 'Macrovascular disease' below and 'Mortality' below and 'Hypoglycemia' below.)

Glycated hemoglobin (A1C) — Selecting an appropriate target glycated hemoglobin (A1C) should be individualized, balancing the anticipated reduction in microvascular and macrovascular complications over time with the immediate risks of hypoglycemia and weight gain.

A reasonable goal of therapy might be an A1C value of ≤7 percent for most patients (using a Diabetes Control and Complications Trial [DCCT]-aligned assay in which the upper limit of normal is 6 percent) [7]. In order to achieve the A1C goal, a fasting glucose of 70 to 120 mg/dL (3.9 to 6.7 mmol/L) and a postprandial glucose (90 to 120 minutes after a meal) less than 180 mg/dL (10 mmol/L) were targeted in the DCCT, but higher achieved levels may suffice (table 1) [8,9]. If it can be safely achieved, tighter targets, such as <6.5 percent, are reasonable, but there are no clinical trial data to support improved long-term clinical outcomes with tighter targets.

The A1C goal should be set somewhat higher (eg, <7.5 or <8 percent, or higher) for patients with a history of severe hypoglycemia or hypoglycemia unawareness, patients with limited life expectancy, very young children or older adults, and individuals with advanced complications or comorbid conditions. (See "Insulin therapy for children and adolescents with type 1 diabetes mellitus", section on 'Target for hemoglobin A1c'.)

Increasing the intensity of glycemic control to achieve A1C levels substantially under the 7 percent threshold is indicated during pregnancy in women with type 1 (and also in type 2 and atypical forms) diabetes since the A1C level in nondiabetic women falls during pregnancy and the demonstrated benefits to the fetus and neonate drive the therapeutic goals. (See "Pregestational (preexisting) diabetes mellitus: Antenatal glycemic control".)

The risk of retinopathy in type 1 diabetes does not plateau at an A1C value of 7 percent (using the DCCT assay or its equivalent). The DCCT established a risk gradient between chronic A1C levels and retinopathy such that for every 10 percent lower A1C (for example, 10 to 9 percent or 9 to 8.1 percent), the risk for retinopathy is reduced by 44 percent [10]. The relationship extends across the entire range of A1C, so that reducing A1C from 7 to 6.3 percent further reduces the risk for retinopathy by 44 percent; however, with lower A1C results, the absolute benefits become progressively smaller (figure 1) at the cost of an increased risk of hypoglycemia (figure 2). Similar results have been established for risk of nephropathy. (See 'Microvascular disease' below and 'Hypoglycemia' below.)

Glycemic variability — The effect of fluctuations in glucose levels within or between days (based on intermittent fingerstick blood glucose determinations or as demonstrated using CGM) on the risk of developing diabetic complications is uncertain. Glucose variability has theoretical clinical implications as it generates free radicals that have been implicated in endothelial damage and the formation of atherosclerotic plaques. Control of short-term glycemic variability, in addition to management of chronic hyperglycemia (as measured by A1C), has been hypothesized to potentially protect against microvascular and macrovascular disease [11,12].

However, analysis of data from the DCCT failed to show that the within-day variability in blood glucose played a role in the development of microvascular complications beyond the influence of the mean glucose [13].

Additional data are needed to provide convincing evidence for a beneficial effect of reducing short-term glycemic variability on the development and progression of microvascular and macrovascular diabetes complications. In a study using CGM, short-term glycemic variability was associated with a higher incidence of hypoglycemia [14]. It would appear that smoother glycemic control is always a reasonable goal in all patients, ie, avoidance of major spikes or dips in blood glucose where possible.

BENEFITS OF INTENSIVE GLYCEMIC CONTROL

Microvascular disease — The prospective Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at lower levels of glycemia results in decreased rates of retinopathy, nephropathy, and neuropathy in type 1 diabetes patients [1,10,15]. Similar findings have been noted in subsequent studies and meta-analyses [16].

As an example, in a meta-analysis of 12 trials evaluating different glycemic targets in patients with type 1 diabetes, intensive glucose control compared with less rigorous, conventional treatment significantly reduced the risk of developing retinopathy (6.2 versus 23.2 percent, relative risk [RR] 0.27), nephropathy (16.3 versus 28.4 percent, RR 0.56), and neuropathy (4.9 versus 13.9 percent, RR 0.35) [17]. The largest trial in the meta-analysis was the DCCT [1]. In this trial, patients with type 1 diabetes were randomly assigned to receive either conventional therapy or intensive insulin therapy, consisting of multiple daily injections or continuous insulin administration using an insulin pump and guided by frequent self-monitoring of blood glucose. Patients with no retinopathy or nephropathy at baseline were evaluated in the primary prevention study, while those with established disease were evaluated in the secondary intervention study.

The median A1C values during the 6.5-year DCCT were 7.2 percent with intensive therapy as opposed to 9.1 percent with conventional therapy; the respective mean blood glucose concentrations were 155 mg/dL (8.6 mmol/L) and 235 mg/dL (12.8 mmol/L). The DCCT provided conclusive evidence that strict glycemic control can both delay the onset of microvascular complications (primary prevention) and slow the rate of progression of already-present complications (secondary intervention).

Following completion of the DCCT in 1993, the conventional treatment group was offered intensive treatment, and 93 percent of DCCT participants (n = 1394) agreed to participate in the observational Epidemiology of Diabetes Interventions and Complications (EDIC) study [2]. The EDIC follow-up study continues to the present. At the end of the DCCT, the conventional treatment group was taught how to perform intensive therapy and all of the participants were returned to their own health care providers for diabetes care. Differences in A1C levels between the original intensive and conventional treatment groups at the end of the DCCT trial (7.2 and 9.1 percent, respectively) narrowed during follow-up (8.1 and 8.2 percent, respectively, by five years and approximately 7.8 to 7.9 in both original treatment groups for the next 20 years) [18-21].

The individual microvascular endpoints of the DCCT/EDIC are discussed immediately below.

Retinopathy — Retinopathy has been chosen as the major endpoint in many of the prospective diabetes trials because it is the most common microvascular complication and is relatively easy to quantify and follow. Standard retinal photographs are taken and scored, based upon the number of microaneurysms, hemorrhages, exudates, and other abnormalities. (See "Diabetic retinopathy: Classification and clinical features" and "Diabetic retinopathy: Pathogenesis".)

Primary prevention – The DCCT demonstrated a substantial benefit of intensive insulin therapy in the primary prevention of diabetic retinopathy; at nine years, the incidence of new retinopathy was 12 percent in the intensive therapy group versus 54 percent in the conventional therapy group [1]. There was a continuous relation between the degree of glycemic control and the incidence of retinopathy (figure 1); the rate of progression increased from 1 per 100 patient-years at a mean A1C value of 5.5 percent up to 9.5 per 100 patient-years at a mean A1C value of 10.5 percent; progressive retinopathy was uncommon at A1C values below 7 percent.

Established retinopathy – In addition to its efficacy in primary prevention, intensive insulin therapy also slows the rate of progression of mild to moderate retinopathy [22]. However, during the first two years of intensive therapy, the DCCT found that retinopathy may worsen (figure 3), most commonly in association with an increased number of soft exudates (due to retinal infarcts in the superficial layers) [23,24]. The mechanism leading to worsening retinopathy in the beginning of the trial remains unclear. (See "Diabetic retinopathy: Pathogenesis", section on 'Growth factors'.)

This early worsening of retinopathy in the DCCT was transient, largely resolving after 18 to 24 months, and there was clear evidence of benefit from intensive therapy when patients with very mild to moderate nonproliferative retinopathy were followed for nine years [22]. The incidence of worsening retinopathy in intensively treated patients was higher than in those receiving conventional therapy at one year (7.4 versus 3 percent) but much lower at nine years (25 versus 53 percent) (figure 3).

Results from the EDIC follow-up study show that intensive insulin therapy for 6.5 years during the DCCT reduced the risk of retinopathy over at least the next 10 years compared with conventional therapy, despite an absence of a difference in A1C values during the post-DCCT trial period [20,25]. This phenomenon has been called "metabolic memory."

Advanced retinopathy – Strict glycemic control is likely of little or no benefit once advanced retinopathy has developed, although high-quality data are lacking. This has been best demonstrated in patients who have undergone pancreas transplantation [26,27]. In one study, for example, 22 transplanted patients (most of whom had advanced retinopathy) were compared with 16 nontransplanted patients with similar disease severity [26]. Despite the attainment and maintenance of normoglycemia in the transplant group, there was no difference between the groups in the rates of progression of retinopathy or visual loss at two years. There was some suggestion of less deterioration at three years in the transplanted patients.

Ocular surgery — In addition to the benefits of intensive insulin therapy in preventing the development and slowing the progression of retinopathy, intensive insulin therapy during the DCCT (6.5 years) resulted in a reduction in the incidence of diabetes-related ocular surgery (cataract extraction; vitrectomy, retinal-detachment surgery, or both; glaucoma-related surgery; cornea- or lens-related surgery; or enucleation) [28]. Over a median total follow-up of 23 years, significantly fewer patients assigned to intensive therapy required diabetes-related ocular surgery (8.9 versus 13.4 percent of patients in the conventional group; risk reduction 48 percent, 95% CI 29-63 percent). The risk reduction with intensive therapy was eliminated after adjustment for A1C level, indicating that the difference in glycemic control explained essentially all of the benefit of intensive therapy in reducing the need for ocular surgery. Although more patients with than without established retinopathy at baseline required ocular surgeries (107 versus 52 patients in the primary prevention group), the RR reduction with intensive insulin therapy was similar for both cohorts (51 and 45 percent risk reduction for established retinopathy and primary prevention groups, respectively) [28].

Nephropathy — Diabetic nephropathy is the most common cause of renal failure in developed countries, although the proportion of patients with type 1 diabetes who progress to end-stage kidney disease has declined compared with previous estimates of 30 to 40 percent. There has also been a reduction in the risk of developing albuminuria and in the progression of diabetic nephropathy in general with optimal medical care for blood pressure, glycemic control, lipid management, and the use of agents that block the renin-angiotensin system. (See "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Incidence and prevalence' and "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Treatment of diabetic kidney disease".)

Lower levels of glycemia can reduce the incidence of new-onset albuminuria and slow the rate of its progression [1,16]. Intensive insulin therapy, by lowering mean plasma glucose, may act in part by reversing the early glomerular hyperfiltration and hypertrophy that are thought to be risk factors for glomerular injury. (See "Diabetic kidney disease: Pathogenesis and epidemiology", section on 'Pathogenesis'.)

Primary prevention – The DCCT included 1365 patients with normal albumin excretion at baseline [1]. At follow-up of up to nine years (mean 6.5 years), intensive therapy led to a significant reduction in the incidence of new-onset moderately increased albuminuria (microalbuminuria, 16.4 versus 23.9 percent, adjusted risk reduction 39 percent) (figure 4) [29]. There was also a significant reduction in new-onset severely increased albuminuria (macroalbuminuria) in the entire study population (3.2 versus 7.2 percent, adjusted risk reduction 51 percent).

Similar to the case with retinopathy, previous intensive treatment with near-normal glycemia during the DCCT had an extended benefit in delaying the onset and progression of diabetic nephropathy, despite an absence of a difference in A1C values during the post-DCCT trial period [19,30].

After eight years of follow-up in EDIC, patients originally assigned to intensive glycemic control were significantly less likely to develop new moderately increased albuminuria (7 versus 16 percent), new severely increased albuminuria (1.4 versus 9 percent), and hypertension (30 versus 40 percent).

After 16 years of follow-up in EDIC (22 years since in the start of the DCCT trial), patients originally assigned to intensive glycemic control were significantly less likely to develop impaired renal function, defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m2 (3.9 versus 7.6 percent) [31]. Renal outcomes such as end-stage kidney disease were relatively uncommon, reducing the ability of the analysis to demonstrate a potential benefit.

Combined renal and pancreas transplantation (the latter to restore normoglycemia) and intensive insulin therapy can delay recurrent diabetic nephropathy in renal allografts, which is further evidence of the protective effect of meticulous glycemic control. (See "Kidney transplantation in diabetic kidney disease", section on 'Recurrent diabetic kidney disease'.)

Secondary prevention – Intensive insulin therapy is also effective at a somewhat later stage after moderately increased albuminuria has developed [24,29,32]. In addition to preventing progression, maintenance of relative normoglycemia often diminishes the degree of protein excretion, although one to two years are usually required for this effect [32,33]. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus", section on 'Glucose control'.)

In contrast to the benefit of aggressive therapy in patients with moderately increased albuminuria, strict glycemic control with intensive insulin therapy may not substantially slow the rate of progressive renal injury once overt albuminuria >300 mg/day) has developed [34,35]. In eight patients with type 1 diabetes who had pancreatic transplantation (three patients had normal albumin excretion, three had microalbuminuria, and two had overt proteinuria), transplantation stabilized but did not improve glomerular structure at five-year follow-up [36,37]. However, benefits were observed at 10 years. (See "Treatment of diabetic kidney disease".)

The apparent lack of substantial benefit from strict glycemic control alone in the setting of overt diabetic nephropathy, although high-quality trial data are sparse, suggests that other factors (such as intraglomerular hypertension and glomerular hypertrophy) may contribute to a larger extent to the progressive glomerular injury in advanced nephropathy. At this late stage, there is often marked glomerulosclerosis. (See "Treatment of diabetic kidney disease".)

Neuropathy — Several prospective studies have demonstrated the ability of improved glycemic control to prevent or slow the progression of neuropathy [16,38,39]. In the DCCT, for example, the following benefits were noted (figure 5) [39]:

The incidence of confirmed clinical neuropathy (defined as findings from the history and physical examination that were confirmed by neurologic testing) was reduced with intensive insulin therapy (5 versus 13 percent).

Intensive insulin therapy also reduced the incidence of abnormal nerve conduction (26 versus 46 percent) and of autonomic dysfunction (4 versus 9 percent).

In patients with possible or definite mild neuropathy at baseline, intensive insulin therapy was associated with an improvement in nerve conduction velocity (figure 6). Whether this translates into a reduction in the incidence of progressive symptomatic neuropathy is not known.

These observations indicate that an intensive insulin regimen to improve glycemic control delays or prevents clinical and physiologic evidence of diabetic neuropathy. In one study, there was a graded effect of hyperglycemia on disease progression, as each 1 percent rise in A1C values was associated with a 1.3 m/sec slowing of nerve conduction at eight years [38].

A number of other potentially modifiable risk factors appear to be associated with the risk of diabetic neuropathy, including hypertriglyceridemia, body mass index, smoking, and hypertension. This issue is discussed in detail elsewhere. (See "Pathogenesis of diabetic polyneuropathy".)

Macrovascular disease — The importance of intensive glycemic control for protection against macrovascular disease in type 1 diabetes was demonstrated in the DCCT/EDIC study.

In the DCCT, there was a nonsignificant trend toward fewer cardiovascular events with intensive therapy (3.2 versus 5.4 percent), although there were few events overall in this young and otherwise healthy group of trial participants [40]. The intensive insulin therapy group also had lower serum low-density lipoprotein (LDL) cholesterol concentrations but, due to the increase in insulin administration, some weight gain.

In the EDIC follow-up study to the DCCT, the group that was originally randomized to intensive insulin therapy experienced substantially fewer fatal and nonfatal cardiovascular events, with a risk reduction of 57 percent (p = 0.02) [2].

In addition to the major adverse cardiac event (MACE) outcomes, an expanded cardiovascular outcome definition "any cardiovascular disease [CVD]," which included MACE and documented angina, or coronary revascularization, was employed. During the entire follow-up period (mean 17 years), there was a lower incidence of any CVD events in patients from the DCCT intensive therapy group (0.38 versus 0.80 events per 100 patient-years with conventional therapy) [2,18]. This represented a 42 percent decrease in any of the designated cardiovascular events (95% CI 9-63 percent).

The difference in levels of glycemic control between the treatment groups, as measured by the A1C during the DCCT, accounted for most of the difference in cardiovascular events between the two groups. Microalbuminuria and albuminuria were also independently associated with cardiovascular outcome, but differences in outcome between the two treatment groups remained after correction for these renal factors. The results indicate that a sustained period of glycemic control (6.5 years in the DCCT study) may have lasting benefit ("metabolic memory") in reducing cardiovascular morbidity and mortality in type 1 diabetes. The patients being followed in EDIC, however, were not necessarily on their original randomized treatment (as reflected by the substantial narrowing in the A1C difference between the groups by one year) [30]. Therefore, other long-term health behaviors may have also played a role.

Mechanisms postulated to account for a benefit of reduced glycemia on cardiovascular events include decreased exposure to advanced glycosylation end products or a secondary consequence of decreased renal disease and autonomic neuropathy that have been implicated in CVD risk. An earlier report from the EDIC study showed that progression of carotid intima-media thickness, a measure of atherosclerosis, was significantly less in those who had received intensive therapy during the DCCT compared with those who had received conventional therapy (progression of intima-media thickness of the common carotid artery 0.032 versus 0.046 mm, respectively) [41]. Comprehensive analyses of the risk factors for CVD in DCCT/EDIC have identified older age and mean A1C levels as the two most important risk factors [42]. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".)

Lower extremity complications — The most important risk factors for developing foot ulcers include neuropathy, foot deformity, and vascular disease (see "Evaluation of the diabetic foot", section on 'Risk factors'). In the DCCT, more intensive insulin therapy (achieved A1C of 7.2 percent) compared with conventional therapy (achieved A1C of 9.1 percent) decreased rates of neuropathy (see 'Neuropathy' above). In the EDIC follow-up study, the incidence of diabetic foot ulcers 23 years post DCCT was also lower in the group that was originally randomized to intensive insulin therapy (7.3 versus 9.6 per 1000 person-years, hazard ratio [HR] 0.77, 95% CI 0.60-0.97) [43]. There were relatively few lower extremity amputations (almost all involving toes) reported during EDIC follow-up, 15 in the intensive group and 21 in the control group (1 and 1.4 per 1000 person-years, respectively, HR 0.70, 95% CI 0.36-1.36).

Mortality — Intensive insulin therapy for 6.5 years during the DCCT reduced the risk of mortality over at least the next 20 years compared with conventional therapy, despite an absence of a difference in A1C values during the post-DCCT trial period [2,18,44].

In the most recent report from DCCT/EDIC, representing a mean follow-up period of 27 years (1429 patients), there was a large relative, albeit modest absolute, reduction in all-cause mortality in patients initially assigned to intensive therapy (43 deaths in the intensive therapy group versus 64 in the conventional group [HR 0.67, 95% CI 0.46-0.99]) [44]. The most common causes of death were CVD (22.4 percent), cancer (19.6 percent), acute diabetes complications (hypoglycemia and diabetic ketoacidosis; 17.8 percent), and accidents or suicide (19.6 percent). All-cause mortality was higher in patients with higher mean A1C levels and in those with renal disease. The mortality rate in the DCCT intensive therapy group was shown to be similar to an age-matched nondiabetic population in the United States [45].

Not all of the results from the DCCT/EDIC are supported by findings from observational studies. As an example, in a study using the Swedish National Diabetes Register, 33,915 patients with and 169,249 without diabetes were followed for a mean of eight years. Compared with individuals without diabetes, the risk of mortality was higher in those with type 1 diabetes [46]. Although the risk was highest in those with the highest A1C values (A1C ≥9.7 percent, HR for all-cause and cardiovascular mortality 8.51 and 10.46, respectively), patients with an A1C ≤6.9 percent also had elevated risk (HR 2.36 and 2.92 for all-cause and cardiovascular mortality, respectively). However, these findings are tempered by the incomplete assessment of A1C levels for many patients during the eight years of observation, making it difficult to determine if there is still an excess risk of death in patients with consistently good glycemic control from time of diagnosis onward.

POTENTIAL OBSTACLES TO INTENSIVE GLYCEMIC CONTROL

Hypoglycemia — The major adverse event associated with intensive glycemic control is hypoglycemia [47]. In the Diabetes Control and Complications Trial (DCCT), hypoglycemia was continuously, but inversely, related to glycemic control, ranging from approximately 105 to 25 episodes per 100 patient-years at mean A1C values of 7 versus 10 percent, respectively (figure 2) [1]. In studies evaluating the benefits of continuous glucose monitoring (CGM) in adults with type 1 diabetes, hypoglycemia (<54 mg/dL [3 mmol/L]) has been shown to occur more frequently, as often as every two to three days [48]. The addition of CGM, and especially CGM that alarms at lower glucose levels, to multiple daily injection or insulin pump therapy and the use of "hybrid" pumps that automatically adjust and interrupts basal rates in the setting of falling glucose levels ("low glucose suspend") have generally lowered the risk of hypoglycemia while achieving target A1C levels [49]. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Types of insulin pumps'.)

Hypoglycemia is more likely to occur in patients if they also develop impaired release of the protective counterregulatory hormones glucagon (which is common after 10 years diabetes duration) and epinephrine, a manifestation of autonomic neuropathy. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Magnitude of the problem' and "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Target A1C and glucose levels in patients with type 1 and 2 diabetes should be tailored to the individual, balancing the reduction in microvascular and macrovascular complications with the risk of hypoglycemia (see 'Glycemic targets' above). Less stringent treatment goals may be appropriate for patients with a history of severe hypoglycemia or risk factors for hypoglycemia. (See "Hypoglycemia in adults with diabetes mellitus", section on 'Strategies to manage hypoglycemia'.)

Weight gain — Weight gain is a potential adverse effect of intensive diabetes therapy in type 1 diabetes, and it occurs when insulin dosing matches nutritional intake and when glycosuria is eliminated. In the DCCT, patients in the intensively treated group gained significantly more weight than those who received conventional therapy (5.1 versus 2.4 kg) [47,50]. At study end, 33 percent of the intensive therapy group was overweight compared with 19 percent of the conventional treatment group [47].

Strategies to minimize weight gain with intensive therapy are reviewed separately. (See "Nutritional considerations in type 1 diabetes mellitus".)

Other considerations — Additional patient-related barriers to implementing intensive glycemic control include the desire to avoid multiple daily injections and self-monitoring of blood glucose, fear of hypoglycemia, misconceptions about insulin treatment, as well as financial concerns due to the high cost of insulin, pumps, and testing supplies. Addressing these obstacles is crucial to timely initiation or intensification of insulin treatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults" and "Society guideline links: Diabetes mellitus in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education: Using insulin (The Basics)")

Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Blood glucose monitoring in diabetes (Beyond the Basics)" and "Patient education: Type 1 diabetes: Insulin treatment (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Glycemic targets – Selecting an appropriate target glycated hemoglobin (A1C) should be individualized, balancing the anticipated reduction in microvascular and macrovascular complications over time with the immediate risks of hypoglycemia and weight gain. A reasonable goal of therapy might be an A1C value of ≤7 percent for most patients (using an assay in which the upper limit of normal is 6 percent). Glycemic targets are generally set somewhat higher for children, adolescents, and older patients with comorbidities or a limited life expectancy and little likelihood of benefit from intensive therapy. Less stringent treatment goals may also be appropriate for patients with a history of severe hypoglycemia or risk factors for hypoglycemia. (See 'Glycated hemoglobin (A1C)' above and 'Hypoglycemia' above.)

Increasing the intensity of glycemic control to achieve A1C levels substantially under the 7 percent threshold is indicated during pregnancy in type 1 (and also type 2) diabetes since the A1C level in nondiabetic women falls during pregnancy and the demonstrated benefits to the fetus and neonate drive the therapeutic goals. (See 'Glycemic targets' above.)

Microvascular disease – The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy aimed at lower levels of glycemia results in decreased rates of retinopathy, nephropathy, and neuropathy in type 1 diabetes patients. (See 'Microvascular disease' above.)

In the Epidemiology of Diabetes Interventions and Complications (EDIC) follow-up study to the DCCT, intensive insulin therapy for 6.5 years during the DCCT reduced the risk of retinopathy and nephropathy over at least the next 20 years compared with conventional therapy, despite an absence of a difference in A1C values during the post-DCCT trial period. This phenomenon has been called "metabolic memory." (See 'Retinopathy' above and 'Nephropathy' above.)

Macrovascular disease – In the EDIC follow-up study, being in the intensive insulin therapy arm of the DCCT was associated with less fatal and nonfatal cardiovascular events and mortality. (See 'Macrovascular disease' above and 'Mortality' above.)

Risks of improving glycemia – The major adverse events associated with intensive glycemic control are hypoglycemia and weight gain. (See 'Potential obstacles to intensive glycemic control' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.

  1. Diabetes Control and Complications Trial Research Group, Nathan DM, Genuth S, et al. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977.
  2. Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353:2643.
  3. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. The Diabetes Control and Complications Trial Research Group. Diabetes 1997; 46:1829.
  4. Al-Kateb H, Mirea L, Xie X, et al. Multiple variants in vascular endothelial growth factor (VEGFA) are risk factors for time to severe retinopathy in type 1 diabetes: the DCCT/EDIC genetics study. Diabetes 2007; 56:2161.
  5. Hosseini SM, Boright AP, Sun L, et al. The association of previously reported polymorphisms for microvascular complications in a meta-analysis of diabetic retinopathy. Hum Genet 2015; 134:247.
  6. Effect of intensive therapy on residual beta-cell function in patients with type 1 diabetes in the diabetes control and complications trial. A randomized, controlled trial. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1998; 128:517.
  7. Holt RIG, DeVries JH, Hess-Fischl A, et al. The Management of Type 1 Diabetes in Adults. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2021; 44:2589.
  8. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes-2021. Diabetes Care 2021; 44:S73.
  9. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014; 37:1048.
  10. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 1995; 44:968.
  11. Brownlee M, Hirsch IB. Glycemic variability: a hemoglobin A1c-independent risk factor for diabetic complications. JAMA 2006; 295:1707.
  12. Ceriello A, Monnier L, Owens D. Glycaemic variability in diabetes: clinical and therapeutic implications. Lancet Diabetes Endocrinol 2019; 7:221.
  13. Lachin JM, Bebu I, Bergenstal RM, et al. Association of Glycemic Variability in Type 1 Diabetes With Progression of Microvascular Outcomes in the Diabetes Control and Complications Trial. Diabetes Care 2017; 40:777.
  14. Monnier L, Wojtusciszyn A, Molinari N, et al. Respective Contributions of Glycemic Variability and Mean Daily Glucose as Predictors of Hypoglycemia in Type 1 Diabetes: Are They Equivalent? Diabetes Care 2020; 43:821.
  15. Molitch ME, Steffes MW, Cleary PA, Nathan DM. Baseline analysis of renal function in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group [corrected]. Kidney Int 1993; 43:668.
  16. Reichard P, Nilsson BY, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993; 329:304.
  17. Fullerton B, Jeitler K, Seitz M, et al. Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev 2014; :CD009122.
  18. Nathan DM, Bayless M, Cleary P, et al. Diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: advances and contributions. Diabetes 2013; 62:3976.
  19. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lachin JM, Genuth S, et al. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000; 342:381.
  20. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 2002; 287:2563.
  21. Nathan DM, DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care 2014; 37:9.
  22. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology 1995; 102:647.
  23. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998; 116:874.
  24. Wang PH, Lau J, Chalmers TC. Meta-analysis of effects of intensive blood-glucose control on late complications of type I diabetes. Lancet 1993; 341:1306.
  25. White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008; 126:1707.
  26. Ramsay RC, Goetz FC, Sutherland DE, et al. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med 1988; 318:208.
  27. Wang Q, Klein R, Moss SE, et al. The influence of combined kidney-pancreas transplantation on the progression of diabetic retinopathy. A case series. Ophthalmology 1994; 101:1071.
  28. DCCT/EDIC Research Group, Aiello LP, Sun W, et al. Intensive diabetes therapy and ocular surgery in type 1 diabetes. N Engl J Med 2015; 372:1722.
  29. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications (DCCT) Research Group. Kidney Int 1995; 47:1703.
  30. Writing Team for the Diabetes Control and Complications Trial/Epidemiology 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 2003; 290:2159.
  31. DCCT/EDIC Research Group, de Boer IH, Sun W, et al. Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 2011; 365:2366.
  32. Feldt-Rasmussen B, Mathiesen ER, Deckert T. Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 1986; 2:1300.
  33. Dahl-Jørgensen K, Bjøro T, Kierulf P, et al. Long-term glycemic control and kidney function in insulin-dependent diabetes mellitus. Kidney Int 1992; 41:920.
  34. Bending JJ, Viberti GC, Watkins PJ, Keen H. Intermittent clinical proteinuria and renal function in diabetes: evolution and the effect of glycaemic control. Br Med J (Clin Res Ed) 1986; 292:83.
  35. Breyer JA. Diabetic nephropathy in insulin-dependent patients. Am J Kidney Dis 1992; 20:533.
  36. Fioretto P, Mauer SM, Bilous RW, et al. Effects of pancreas transplantation on glomerular structure in insulin-dependent diabetic patients with their own kidneys. Lancet 1993; 342:1193.
  37. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339:69.
  38. Amthor KF, Dahl-Jørgensen K, Berg TJ, et al. The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo Study. Diabetologia 1994; 37:579.
  39. The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann Intern Med 1995; 122:561.
  40. Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 1995; 75:894.
  41. Nathan DM, Lachin J, Cleary P, et al. Intensive diabetes therapy and carotid intima-media thickness in type 1 diabetes mellitus. N Engl J Med 2003; 348:2294.
  42. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group. Risk Factors for Cardiovascular Disease in Type 1 Diabetes. Diabetes 2016; 65:1370.
  43. Boyko EJ, Zelnick LR, Braffett BH, et al. Risk of Foot Ulcer and Lower-Extremity Amputation Among Participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study. Diabetes Care 2022; 45:357.
  44. Writing Group for the DCCT/EDIC Research Group, Orchard TJ, Nathan DM, et al. Association between 7 years of intensive treatment of type 1 diabetes and long-term mortality. JAMA 2015; 313:45.
  45. Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Mortality in Type 1 Diabetes in the DCCT/EDIC Versus the General Population. Diabetes Care 2016; 39:1378.
  46. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type 1 diabetes. N Engl J Med 2014; 371:1972.
  47. Adverse events and their association with treatment regimens in the diabetes control and complications trial. Diabetes Care 1995; 18:1415.
  48. Heinemann L, Freckmann G, Ehrmann D, et al. Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE): a multicentre, randomised controlled trial. Lancet 2018; 391:1367.
  49. O'Connell J, Nathan DM, O'Brien T, O'Keeffe DT. Treatment of Diabetes - To Pump or Not to Pump. N Engl J Med 2021; 385:2092.
  50. Weight gain associated with intensive therapy in the diabetes control and complications trial. The DCCT Research Group. Diabetes Care 1988; 11:567.
Topic 1751 Version 36.0

References