Diabetes Mellitus: Complications¶

Chapter 417 | Part 12: Endocrinology and Metabolism · Part 12 – Endocrinology & Metabolism

Detailed clinical reference synthesised from Harrison's Principles of Internal Medicine, 22nd Edition

🔑 Key Clinical Points¶

Microvascular complications (retinopathy, neuropathy, nephropathy) result from chronic hyperglycemia; macrovascular complications (ASCVD, PAD, CVD) share pathophysiology with general population but are accelerated by insulin resistance.
DCCT and UKPDS trials established the 'legacy effect' of glycemic control, reducing complications for 10+ years even after glycemic control normalizes.
Blood pressure target is <130/80 mmHg; ACE inhibitors or ARBs are preferred for albuminuria.
SGLT2 inhibitors reduce CKD progression and cardiovascular events; GLP-1 receptor agonists (e.g., semaglutide) improve kidney outcomes and reduce CV death.
Retinopathy screening begins 5 years after type 1 DM onset or at diagnosis of type 2 DM; annual dilated eye exams are required.
Neuropathy screening begins 5 years after type 1 DM onset or at diagnosis of type 2 DM; aims to detect loss of protective sensation (LOPS).
Gestational diabetes mellitus (GDM) complicates ~7% of pregnancies; screening recommended between weeks 24 and 28.
Pregnancy in known DM requires preconception HbA1c <6.5% to reduce fetal malformation risk (4-10 times increased with uncontrolled DM).
Transient worsening of established retinopathy may occur during the first 6-12 months of improved glycemic control.
Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) and stage 5 CKD requiring renal replacement therapy.
Avoidance of hypoglycemia is critical in older adults; HbA1c goals may be <8.0–8.5% for those with complex health or cognitive impairment.
Diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded.

📑 Table of Contents¶

1. DEFINITION & OVERVIEW
1.1 Classification of Complications
1.2 Epidemiology & Risk Factors
2. ETIOLOGY & PATHOPHYSIOLOGY
2.1 Metabolic Memory
3. CLINICAL FEATURES
3.1 Ophthalmologic Complications
3.2 Renal Complications
3.3 Neuropathy
3.4 Reproductive Issues
4. DIFFERENTIAL DIAGNOSIS
4.1 Neuropathy Differential
4.2 Nephropathy Differential
5. INVESTIGATIONS & DIAGNOSIS
5.1 Screening Intervals
5.2 Diagnostic Criteria for Retinopathy
6. MANAGEMENT & TREATMENT
6.1 Glycemic Control Targets
7. PROGNOSIS & COMPLICATIONS
8. SPECIAL CONSIDERATIONS
9. KEY PEARLS & CLINICAL TRAPS
10. WHAT TO LOOK FOR — DIAGNOSTIC CLUES
10.1 Retinopathy Clues
10.2 Nephropathy Clues
10.3 Neuropathy Clues
11. WHAT EXCLUDES THE DIAGNOSIS
11.1 Neuropathy Exclusion
11.2 Nephropathy Exclusion
Figures & Illustrations

📋 Figures in This Chapter¶

#	Type	Description
1	🖼 Figure	Time course of development of diabetic nephropathy
2	🖼 Figure	Relationship of glycemic control and diabetes duration to diabetic retinopathy
3	🖼 Figure	Diabetic glomerular changes in a patient with type 1 diabetes are shows...
4	🖼 Figure	Diabetic retinopathy results in scattered hemorrhages, yellow exudates, and neovascularization

1. DEFINITION & OVERVIEW¶

Diabetes-related complications affect many organ systems and are responsible for most of the morbidity and mortality associated with the disease. For many years in the United States, diabetes has been a leading cause of new blindness in adults, renal failure, and nontraumatic lower extremity amputation and is a leading contributor to coronary heart disease (CHD). Diabetes-associated microvascular complications usually do not appear until the second decade of hyperglycemia. In contrast, diabetes-associated atherosclerotic cardiovascular disease (ASCVD) risk, related in part to insulin resistance and its resultant dyslipidemia, may develop before hyperglycemia is established. Because type 2 DM often has a long asymptomatic period of hyperglycemia before diagnosis, many individuals with type 2 DM have both glucose-related and insulin resistance–related complications at the time of diagnosis.

1.1 Classification of Complications¶

Diabetes-related complications can be divided into vascular and nonvascular complications and are similar for type 1 and type 2 DM (Table 417-1). The vascular complications of DM are further subdivided into microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications (ASCVD, peripheral arterial disease [PAD], cerebrovascular disease, and heart failure). Microvascular complications are diabetes specific, whereas macrovascular complications have additional pathophysiologic features that are shared with the general population. Nonvascular complications include infections, skin changes, cheiroarthropathy, hearing loss, and increased risk of fractures, dementia, and impaired cognitive function.

Category	Specific Complications
Microvascular	Eye disease (Retinopathy [nonproliferative/proliferative], Macular edema, Cataracts, Glaucoma); Neuropathy (Sensory and motor [mono- and polyneuropathy], Autonomic); Nephropathy (albuminuria and declining renal function)
Macrovascular	Coronary heart disease, Peripheral arterial disease, Cerebrovascular disease, Heart failure
Other	Gastrointestinal (gastroparesis, diarrhea), Genitourinary (uropathy/sexual dysfunction), Dermatologic, Infectious
Other comorbid conditions associated with type 1 or type 2 diabetes (relationship to hyperglycemia is uncertain)	Depression, Obstructive sleep apnea, Fatty liver disease, Hip fracture, Osteoporosis, Cognitive impairment or dementia, Low testosterone in men

1.2 Epidemiology & Risk Factors¶

Diabetes-related complications can be prevented or mitigated with aggressive glycemic, lipid, and blood pressure control, as well as efforts at early detection. Diagnosis of type 2 DM at younger age increases diabetes-related complications. One estimate indicated three to four years of reduced life expectancy for every decade of earlier diabetes diagnosis. This emphasizes the critical role of diabetes prevention or delay. Approximately 20–40% of patients with diabetes develop diabetic nephropathy. Known risk factors include a family history of diabetic nephropathy with additional genetic or environmental susceptibility factors likely contributing. Smoking accelerates the decline in renal function. The presence of ASCVD, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease. Diabetic nephropathy and stage 5 CKD secondary to DM develop more commonly in Black, Native American, and Hispanic individuals.

2. ETIOLOGY & PATHOPHYSIOLOGY¶

Chronic hyperglycemia is the important etiologic factor leading to complications of DM, but the mechanism(s) by which it leads to such diverse cellular and organ dysfunction is unknown. The complications are likely multifactorial with an emerging hypothesis that hyperglycemia leads to epigenetic changes that influence gene expression in affected cells. Chronic hyperglycemia leads to formation of advanced glycosylation end products (AGEs; e.g., pentosidine, glucosepane, and carboxymethyllysine), which bind to specific cell surface receptor and/or the nonenzymatic glycosylation of intra- and extracellular proteins, leading to cross-linking of proteins, glomerular dysfunction, endothelial dysfunction, altered extracellular matrix composition, and accelerated atherosclerosis. Growth factors may play an important role in some diabetes-related microvascular complications. For example, vascular endothelial growth factor A (VEGF-A) is increased locally in diabetic proliferative retinopathy, decreases after laser photocoagulation, and is the target inhibited by intravitreous injection therapy. A possible unifying mechanism is that hyperglycemia leads to increased production of reactive oxygen species or superoxide in the mitochondria and this may activate several pathways. Although hyperglycemia serves as the initial trigger for complications of diabetes, it is still unknown whether the same pathophysiologic processes are operative in all complications or whether some pathways predominate in certain organs. The mechanisms of diabetes-related macrovascular complications including MI and stroke also include traditional cardiovascular risk factors (dyslipidemia, hypertension), insulin resistance, and inflammation. In T2DM, insulin resistance is present years prior to diagnosis and is associated with obesity and ectopic accumulation of lipids and fat in liver and muscle. Additionally, insulin fails to appropriately suppress lipolysis from adipose tissue, which results in increased delivery of fatty acids to liver, muscle, endothelial cells, and cardiac tissues, leading to tissue accumulation of triglycerides, diacylglycerol, and ceramides.

2.1 Metabolic Memory¶

In both the DCCT and the UKPDS, cardiovascular events were reduced at follow-up of >10 years, even though the improved glycemic control was not maintained. This legacy effect for a positive impact of a period of improved glycemic control on later diabetes complications has been termed metabolic memory, and this legacy effect was estimated to be 10 years or more. Of note, despite long-standing DM, some individuals never develop retinopathy or nephropathy, suggesting a genetic susceptibility for developing particular complications.

3. CLINICAL FEATURES¶

Diabetes-related complications affect many organ systems and are responsible for most of the morbidity and mortality associated with the disease. For many years in the United States, diabetes has been a leading cause of new blindness in adults, renal failure, and nontraumatic lower extremity amputation and is a leading contributor to coronary heart disease (CHD).

3.1 Ophthalmologic Complications¶

DM is the leading cause of new cases of blindness between the ages of 20 and 74 in the United States. Glaucoma and cataracts occur earlier and more frequently in individuals with diabetes. Severe vision loss is primarily the result of progressive diabetic retinopathy, which leads to significant macular edema and new blood vessel formation. Diabetic retinopathy is classified into two stages: nonproliferative and proliferative. Nonproliferative diabetic retinopathy usually appears late in the first decade or early in the second decade of hyperglycemia and is marked by retinal vascular microaneurysms, blot hemorrhages, and cotton-wool spots. Mild nonproliferative retinopathy may progress to more extensive disease, characterized by changes in venous vessel caliber, intraretinal microvascular abnormalities, and more numerous microaneurysms and hemorrhages. The pathophysiologic mechanisms invoked in nonproliferative retinopathy include loss of retinal pericytes, increased in the retinal vascular permeability, alterations in retinal blood flow, and abnormal retinal microvasculature, all of which can lead to retinal ischemia. The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy. These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Not all individuals with nonproliferative retinopathy go on to develop proliferative retinopathy, but the more severe the nonproliferative disease, the greater is the chance of evolution to proliferative retinopathy within 5 years. Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors. Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control.

3.2 Renal Complications¶

Diabetic nephropathy is the leading cause of chronic kidney disease (CKD) and stage 5 CKD (e.g., end-stage renal disease) requiring renal replacement therapy. CKD in individuals with DM is associated with an increased risk of cardiovascular disease, and the prognosis of individuals with diabetes on dialysis is poor. Individuals with type 1 DM and diabetic nephropathy commonly also have diabetic retinopathy; this association is less pronounced in type 2 DM. The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease. Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) may occur in type 1 or 2 DM. These individuals develop a propensity to hyperkalemia and acidemia, which may be exacerbated by medications (especially angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and mineralocorticoid receptor antagonists). Patients with DM are predisposed to radiocontrast-induced nephrotoxicity. Risk factors for radiocontrast-induced nephrotoxicity are preexisting nephropathy and volume depletion. Individuals with DM undergoing radiographic procedures with iodinated contrast dye should be well hydrated before and after dye exposure, and the serum creatinine should be monitored for 24–48 h following the procedure.

3.3 Neuropathy¶

Diabetic neuropathy, which occurs in ~50% of individuals with long-standing type 1 and type 2 DM, manifests as a diffuse neuropathy (distal symmetrical polyneuropathy and/or autonomic neuropathy), a mononeuropathy, and/or a radiculopathy/polyradiculopathy. As with other complications of DM, the development of neuropathy correlates more with the duration of diabetes and glycemic control. Additional risk factors are body mass index (BMI) (the greater the BMI, the greater the risk of neuropathy) and smoking. The presence of ASCVD, elevated triglycerides, and hypertension is also associated with diabetic peripheral neuropathy. Both myelinated and unmyelinated nerve fibers are lost. Because the clinical features of diabetic neuropathy are similar to those of other neuropathies, the diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded.

3.4 Reproductive Issues¶

Reproductive capacity in either men or women with DM appears to be normal. Menstrual cycles may be associated with alterations in glycemic control in women with DM. Pregnancy is associated with marked insulin resistance; the increased insulin requirements often precipitate DM and lead to the diagnosis of gestational diabetes mellitus (GDM). Glucose, which at high levels is a teratogen to the developing fetus, readily crosses the placenta, but insulin does not. Thus, hyperglycemia from the maternal circulation may stimulate insulin secretion in the fetus. The anabolic and growth effects of insulin may result in macrosomia. GDM complicates ~7% (range 1–14%) of pregnancies. The incidence of GDM is greatly increased in certain racial and ethnic groups, including Black and Hispanic, consistent with a similar increased risk of type 2 DM. Current recommendations advise screening for glucose intolerance between weeks 24 and 28 of pregnancy in women not known to have diabetes. Therapy for GDM is similar to that for individuals with pregnancy-associated diabetes and involves MNT and insulin, if hyperglycemia persists. Oral glucose-lowering agents are not approved for use during pregnancy, but studies using metformin or glyburide have shown efficacy and have not found toxicity. With current practices, the morbidity and mortality rates of the mother with GDM and the fetus are not different from those in the nondiabetic population. Individuals who develop GDM are at marked increased risk for developing type 2 DM in the future and should be screened periodically for DM. Most individuals with GDM revert to normal glucose tolerance after delivery, but some will continue to have overt diabetes or impairment of glucose tolerance after delivery. In addition, children of women with GDM appear to be at risk for obesity and glucose intolerance and have an increased risk of diabetes beginning in the later stages of adolescence.

4. DIFFERENTIAL DIAGNOSIS¶

Diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded. The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease.

4.1 Neuropathy Differential¶

Because the clinical features of diabetic neuropathy are similar to those of other neuropathies, the diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded.

4.2 Nephropathy Differential¶

The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease.

5. INVESTIGATIONS & DIAGNOSIS¶

Regular, comprehensive eye examinations are essential for all individuals with DM. Most diabetic eye disease can be successfully treated if detected early. Routine, nondilated eye examinations by the primary care provider or diabetes specialist are inadequate to detect diabetic eye disease, which requires a dilated eye exam performed by an optometrist or ophthalmologist or by retinal photography with remote reading. Subsequent management should be by a retinal specialist. Screening for albuminuria should commence 5 years after type 1 DM onset and at the time of diagnosis of type 2 DM and be performed annually. An elevated UACR should be confirmed on two to three occasions over a 3- to 6-month period since it can be falsely elevated by strenuous exercise at a time close to its measurement, infection, fever, congestive heart failure, marked hyperglycemia, marked hypertension, or prostate disease. The urine protein measure by routine urinalysis does not detect low levels of albumin excretion. Nephrology consultation is indicated when the estimated GFR is 300 mg/g creatinine, or if there are atypical features such as hematuria or rapidly declining renal function. The ADA suggests a protein intake of 0.8 g/kg of body weight per day in individuals with diabetic kidney disease.

5.1 Screening Intervals¶

Screening for albuminuria should commence 5 years after type 1 DM onset and at the time of diagnosis of type 2 DM and be performed annually. Annual screening for DSPN should begin 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM and is aimed at detecting loss of protective sensation (LOPS).

5.2 Diagnostic Criteria for Retinopathy¶

Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors. Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control. Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Fluorescein angiography and optical coherence tomography are useful to detect macular edema, which is associated with an increased chance of moderate visual loss over the next 3 years.

6. MANAGEMENT & TREATMENT¶

The optimal therapy for diabetic nephropathy is prevention by control of glycemia and blood pressure (blood pressure <130/80 mmHg). Renin-angiotensin-aldosterone system inhibitors do not prevent the development of diabetic kidney disease if hypertension or albuminuria is not present. Interventions effective in slowing progression of albuminuria and the decline in kidney function include (1) improved glycemic control, (2) strict blood pressure control, (3) administration of an ACE inhibitor or ARB, (4) in individuals with type 2 DM, administration of a sodium-glucose cotransporter 2 (SGLT-2) inhibitor and (5) administration of a mineralocorticoid receptor antagonist (especially finerenone). Dyslipidemia should also be treated. Improved glycemic control reduces the rate at which albuminuria appears and progresses in type 1 and type 2 DM. However, once there is a moderate level of albuminuria, it becomes more difficult for improved glycemic control to slow progression of renal disease, although 10 years of normoglycemia resulting from pancreas transplantation may lead to regression of mesangial glomerular lesions. During the late phase of declining renal function, insulin requirements may fall as the kidney is a site of insulin degradation. As the GFR decreases with progressive nephropathy, the use and dose of glucose-lowering agents should be reevaluated. Some glucose-lowering medications (sulfonylureas and metformin) are contraindicated in advanced renal insufficiency, while others may require dose adjustment (glinides and DPP-4 inhibitors). SGLT2 inhibitors are not effective with eGFR < 20 mL/min/1.73 m2. Metformin should be held until postintervention confirmation of preserved kidney function.

6.1 Glycemic Control Targets¶

In choosing medications for diabetes, the adverse effects should be considered (especially heart failure, renal insufficiency, propensity for hypoglycemia, etc.). Critical to diabetes management in all older individuals is the avoidance of hypoglycemia, which can worsen underlying cognitive impairment or CVD. In the former, the HbA1c goal (<7.0–7.5%) and selected therapies may be similar to younger individuals, whereas in an individual with complex/poor health or cognitive impairment, an HbA1c goal of <8.0–8.5% would be reasonable. For pregnancy, intensive insulin therapy and near-normalization of the HbA1c (<6.5%) are essential.

7. PROGNOSIS & COMPLICATIONS¶

The DCCT phase demonstrated that improvement of glycemic control reduced nonproliferative and proliferative retinopathy (47% reduction), albuminuria (39% reduction), clinical nephropathy (54% reduction), and neuropathy (60% reduction). Improved glycemic control also slowed the progression of early diabetic complications. During the DCCT phase, weight gain (4.6 kg) and severe hypoglycemia (requiring assistance of another person to treat) were more common in the intensive therapy group. The benefits of an improvement in glycemic control occurred over the entire range of elevated HbA1c values. The results of the DCCT predicted that individuals in the intensive diabetes management group would gain 7.7 additional years of vision, 5.8 additional years free from end-stage renal disease, and 5.6 years free from lower extremity amputations. If all complications of DM were combined, individuals in the intensive diabetes management group would experience >15.3 more years of life without significant microvascular complications of DM, compared to individuals who received standard therapy. This translates into an additional 5.1 years of life expectancy for individuals in the intensive diabetes management group. The 30-year follow-up data in the intensively treated group show a continued reduction in retinopathy, nephropathy, and cardiovascular disease. For example, individuals in the intensive therapy group had a 57% reduction in cardiovascular events (nonfatal myocardial infarction [MI], stroke, or death from a cardiovascular event) and a 33% reduction in the mortality rate, even though their subsequent glycemic control was the same as those in the conventional diabetes management group after the DCCT phase ended (year 6.5). During the EDIC phase, fewer in the intensely treated cohort became blind, lost a limb to amputation, or required dialysis. Other complications of diabetes, including autonomic neuropathy, bladder and sexual dysfunction, cardiac autonomic neuropathy, cheiroarthropathy and hearing loss, were reduced in the intensive therapy group. These results are even more impressive when one considers that initial DCCT results were reported in 1993 and diabetes therapy during the trial was quite different in terms of insulin formulations and delivery systems.

8. SPECIAL CONSIDERATIONS¶

Critical to diabetes management in all older individuals is the avoidance of hypoglycemia, which can worsen underlying cognitive impairment or CVD. In the former, the HbA1c goal (<7.0–7.5%) and selected therapies may be similar to younger individuals, whereas in an individual with complex/poor health or cognitive impairment, an HbA1c goal of <8.0–8.5% would be reasonable. In choosing medications for diabetes, the adverse effects should be considered (especially heart failure, renal insufficiency, propensity for hypoglycemia, etc.).

9. KEY PEARLS & CLINICAL TRAPS¶

Diagnosis of type 2 DM at younger age increases diabetes-related complications. One estimate indicated three to four years of reduced life expectancy for every decade of earlier diabetes diagnosis. This emphasizes the critical role of diabetes prevention or delay. The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development and slow the progression of retinopathy in individuals with either type 1 or type 2 DM. Paradoxically, during the first 6–12 months of improved glycemic control, established diabetic retinopathy may transiently worsen. Fortunately, this progression is temporary, and in the long term, improved glycemic control is associated with less diabetic retinopathy. When associated with a marked glycemic improvement, glucagon-like peptide 1 (GLP-1) receptor agonists have been associated with an increased risk of worsening diabetic retinopathy; this should be considered when choosing agents to improve in glycemic control. Individuals with retinopathy may be candidates for prophylactic laser photocoagulation when initiating intensive therapy, and especially prior to pancreateas or islet transplantation that can rapidly normalize glycemia. Women with type 1 or type 2 DM who are planning pregnancy should be screened prior to and during pregnancy. Once advanced retinopathy is present, improved glycemic control imparts less benefit. Appropriate ophthalmologic care can prevent most blindness. Lowering elevated levels of triglycerides with fenofibrate may also reduce the progression of retinopathy. Regular, comprehensive eye examinations are essential for all individuals with DM. Most diabetic eye disease can be successfully treated if detected early. Treatment of severe nonproliferative or proliferative retinopathy or macular edema with panretinal laser photocoagulation therapy and/or anti-VEGF therapy (intravitreous injection) usually is successful in preserving vision. Aspirin therapy does not appear to influence the natural history of diabetic retinopathy, and antiplatelet agents and anticoagulation may be continued in patients receiving intravitreal injections of anti-VEGF agents. Patients with severe proliferative retinopathy with vitreous hemorrhage and/or traction involving the macula often require surgical vitrectomy. The optimal therapy for diabetic nephropathy is prevention by control of glycemia and blood pressure (blood pressure 300 mg/g creatinine is to reduce the UACR by 30%. To reduce CKD progression and cardiovascular events in individuals with CKD, type 2 DM, and an eGFR >20 mL/min per 1.73 m2, the addition of an SGLT-2 inhibitor, while continuing an ACE inhibitor or ARB, is recommended with any level of albuminuria. A GLP-1 agonist or a nonsteroidal mineralocorticoid or receptor antagonist like finerenone will also reduce cardiovascular risk in individuals with type 2 DM and CKD. The GLP-1 receptor agonist semaglutide improves kidney outcomes and reduces death from cardiovascular causes in type 2 DM and CKD. SGLT-2 inhibitors are also discussed in Chap. 265, especially the use in heart failure treatment or prevention, and in Chap. 322, as related to CKD. Because of the elevated risk of euglycemic diabetic ketoacidosis, SGLT-2 inhibitors in individuals with type 1 DM and insulin-deficient type 2 DM should be used with caution and include patient education about ketone monitoring and recognizing diabetic ketoacidosis. Nephrology consultation is indicated when the estimated GFR is 300 mg/g creatinine, or if there are atypical features such as hematuria or rapidly declining renal function. The ADA suggests a protein intake of 0.8 g/kg of body weight per day in individuals with diabetic kidney disease. Complications of ASCVD are the leading cause of death in diabetic individuals with nephropathy; hyperlipidemia should be treated aggressively. Preemptive (before dialysis) kidney transplantation from a living donor should be considered in those nearing stage 5 CKD (e.g., end-stage renal disease) and for those with type 1 DM or insulin deficient type 2 DM, simultaneous pancreas-kidney transplantation from a deceased donor may be an option. As compared with nondiabetic individuals, hemodialysis in patients with DM is associated with more frequent complications, such as hypotension (due to autonomic neuropathy or loss of reflex tachycardia), more difficult vascular access, accelerated progression of retinopathy, and greater mortality. Prevention of diabetic neuropathy is critical through improved glycemic control. Treatment of diabetic neuropathy is less than satisfactory. Lifestyle modifications (exercise, diet) have some efficacy in DSPN in type 2 DM and hypertension and hypertriglyceridemia should be treated. Efforts to improve glycemic control in long-standing diabetes may be limited by hypoglycemia unawareness. Patients should avoid neurotoxins (including alcohol) and smoking and consider supplementation with vitamins for possible deficiencies (B12, folate). Metformin may reduce intestinal absorption of vitamin B12 in type 2 DM, and pernicious anemia is more common in type 1 DM where it is associated with anti–parietal cell autoantibodies and may require sublingual or parenteral B12 replacement. Patients should be educated that loss of sensation in the foot increases the risk of foot ulceration and falls. Diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded. The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors. Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control. Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Fluorescein angiography and optical coherence tomography are useful to detect macular edema, which is associated with an increased chance of moderate visual loss over the next 3 years. The natural history of diabetic nephropathy is characterized by a sequence of events that was initially defined for individuals with type 1 DM but appears similar in type 2 DM. Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the estimated glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. Once there is marked albuminuria and a reduction in GFR, these pathologic changes are likely irreversible. The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development and slow the progression of retinopathy in individuals with either type 1 or type 2 DM. Paradoxically, during the first 6–12 months of improved glycemic control, established diabetic retinopathy may transiently worsen. Fortunately, this progression is temporary, and in the long term, improved glycemic control is associated with less diabetic retinopathy. When associated with a marked glycemic improvement, glucagon-like peptide 1 (GLP-1) receptor agonists have been associated with an increased risk of worsening diabetic retinopathy; this should be considered when choosing agents to improve in glycemic control. Individuals with retinopathy may be candidates for prophylactic laser photocoagulation when initiating intensive therapy, and especially prior to pancreateas or islet transplantation that can rapidly normalize glycemia. Women with type 1 or type 2 DM who are planning pregnancy should be screened prior to and during pregnancy. Once advanced retinopathy is present, improved glycemic control imparts less benefit. Appropriate ophthalmologic care can prevent most blindness. Lowering elevated levels of triglycerides with fenofibrate may also reduce the progression of retinopathy. Regular, comprehensive eye examinations are essential for all individuals with DM. Most diabetic eye disease can be successfully treated if detected early. Treatment of severe nonproliferative or proliferative retinopathy or macular edema with panretinal laser photocoagulation therapy and/or anti-VEGF therapy (intravitreous injection) usually is successful in preserving vision. Aspirin therapy does not appear to influence the natural history of diabetic retinopathy, and antiplatelet agents and anticoagulation may be continued in patients receiving intravitreal injections of anti-VEGF agents. Patients with severe proliferative retinopathy with vitreous hemorrhage and/or traction involving the macula often require surgical vitrectomy. The optimal therapy for diabetic nephropathy is prevention by control of glycemia and blood pressure (blood pressure 300 mg/g creatinine is to reduce the UACR by 30%. To reduce CKD progression and cardiovascular events in individuals with CKD, type 2 DM, and an eGFR >20 mL/min per 1.73 m2, the addition of an SGLT-2 inhibitor, while continuing an ACE inhibitor or ARB, is recommended with any level of albuminuria. A GLP-1 agonist or a nonsteroidal mineralocorticoid or receptor antagonist like finerenone will also reduce cardiovascular risk in individuals with type 2 DM and CKD. The GLP-1 receptor agonist semaglutide improves kidney outcomes and reduces death from cardiovascular causes in type 2 DM and CKD. SGLT-2 inhibitors are also discussed in Chap. 265, especially the use in heart failure treatment or prevention, and in Chap. 322, as related to CKD. Because of the elevated risk of euglycemic diabetic ketoacidosis, SGLT-2 inhibitors in individuals with type 1 DM and insulin-deficient type 2 DM should be used with caution and include patient education about ketone monitoring and recognizing diabetic ketoacidosis. Nephrology consultation is indicated when the estimated GFR is 300 mg/g creatinine, or if there are atypical features such as hematuria or rapidly declining renal function. The ADA suggests a protein intake of 0.8 g/kg of body weight per day in individuals with diabetic kidney disease. Complications of ASCVD are the leading cause of death in diabetic individuals with nephropathy; hyperlipidemia should be treated aggressively. Preemptive (before dialysis) kidney transplantation from a living donor should be considered in those nearing stage 5 CKD (e.g., end-stage renal disease) and for those with type 1 DM or insulin deficient type 2 DM, simultaneous pancreas-kidney transplantation from a deceased donor may be an option. As compared with nondiabetic individuals, hemodialysis in patients with DM is associated with more frequent complications, such as hypotension (due to autonomic neuropathy or loss of reflex tachycardia), more difficult vascular access, accelerated progression of retinopathy, and greater mortality. Prevention of diabetic neuropathy is critical through improved glycemic control. Treatment of diabetic neuropathy is less than satisfactory. Lifestyle modifications (exercise, diet) have some efficacy in DSPN in type 2 DM and hypertension and hypertriglyceridemia should be treated. Efforts to improve glycemic control in long-standing diabetes may be limited by hypoglycemia unawareness. Patients should avoid neurotoxins (including alcohol) and smoking and consider supplementation with vitamins for possible deficiencies (B12, folate). Metformin may reduce intestinal absorption of vitamin B12 in type 2 DM, and pernicious anemia is more common in type 1 DM where it is associated with anti–parietal cell autoantibodies and may require sublingual or parenteral B12 replacement. Patients should be educated that loss of sensation in the foot increases the risk of foot ulceration and falls. Diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded. The presence of CKD without retinopathy in type 1 DM should prompt investigation for alternative causes of kidney disease. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors. Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control. Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Fluorescein angiography and optical coherence tomography are useful to detect macular edema, which is associated with an increased chance of moderate visual loss over the next 3 years. The natural history of diabetic nephropathy is characterized by a sequence of events that was initially defined for individuals with type 1 DM but appears similar in type 2 DM. Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the estimated glomerular filtration rate (GFR). During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal. Once there is marked albuminuria and a reduction in GFR, these pathologic changes are likely irreversible.

10. WHAT TO LOOK FOR — DIAGNOSTIC CLUES¶

The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy. These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment. Not all individuals with nonproliferative retinopathy go on to develop proliferative retinopathy, but the more severe the nonproliferative disease, the greater is the chance of evolution to proliferative retinopathy within 5 years. Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy. Fluorescein angiography and optical coherence tomography are useful to detect macular edema, which is associated with an increased chance of moderate visual loss over the next 3 years. Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors. Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control.

10.1 Retinopathy Clues¶

The appearance of neovascularization in response to retinal hypoxia is the hallmark of proliferative diabetic retinopathy.
These newly formed vessels appear near the optic nerve and/or macula and rupture easily, leading to vitreous hemorrhage, fibrosis, and ultimately retinal detachment.
Not all individuals with nonproliferative retinopathy go on to develop proliferative retinopathy, but the more severe the nonproliferative disease, the greater is the chance of evolution to proliferative retinopathy within 5 years.
Clinically significant macular edema can occur in the context of nonproliferative or proliferative retinopathy.
Fluorescein angiography and optical coherence tomography are useful to detect macular edema, which is associated with an increased chance of moderate visual loss over the next 3 years.
Duration of DM and degree of glycemic control are the best predictors of the development of retinopathy; hypertension, nephropathy, and dyslipidemia are also risk factors.
Although there is genetic susceptibility for retinopathy, it confers less influence than either the duration of DM or the degree of glycemic control.

10.2 Nephropathy Clues¶

The natural history of diabetic nephropathy is characterized by a sequence of events that was initially defined for individuals with type 1 DM but appears similar in type 2 DM.
Glomerular hyperperfusion and renal hypertrophy occur in the first years after the onset of DM and are associated with an increase of the estimated glomerular filtration rate (GFR).
During the first 5 years of DM, thickening of the glomerular basement membrane, glomerular hypertrophy, and mesangial volume expansion occur as the GFR returns to normal.
Once there is marked albuminuria and a reduction in GFR, these pathologic changes are likely irreversible.

10.3 Neuropathy Clues¶

DSPN, the most common form of diabetic neuropathy, most frequently presents with distal sensory loss and pain, but up to 50% of patients do not have symptoms of neuropathy.
Symptoms may include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally.
Pain typically involves the lower extremities, is usually present at rest, and worsens at night.
Physical examination often reveals sensory loss (to 10-g monofilament and/or vibration), loss of ankle deep-tendon reflexes, abnormal position sense, and muscular atrophy or foot drop.
Annual screening for DSPN should begin 5 years after diagnosis of type 1 DM and at the time of diagnosis of type 2 DM and is aimed at detecting loss of protective sensation (LOPS).
LOPS and DSPN are major risk factors for foot ulceration and falls due to small and large nerve fiber dysfunction and predispose to lower extremity amputation.

11. WHAT EXCLUDES THE DIAGNOSIS¶