Course of disease

Chronic hyperglycemia lead to many complications

Chronic hyperglycemia is the important etiologic factor leading to complications of diabetes mellitus (DM), but the mechanism(s) by which it leads to such diverse cellular and organ dysfunction is unknown. An emerging hypothesis is that hyperglycemia leads to epigenetic changes that influence gene expression in affected cells. Other hypotheses are that chronic hyperglycemia leads to formation of advanced glycosylation end products (AGEs), such as pentosidine, glucosepane, and carboxymethyl-lysine, which bind to specific cell surface receptor and/or the non-enzymatic glycosylation of intra- and extracellular proteins, leading to cross-linking of proteins, accelerated atherosclerosis, glomerular dysfunction, endothelial dysfunction, and altered extracellular matrix composition.

DM-related complications can be divided into vascular and nonvascular complications and are similar for type 1 and type 2 DM. The vascular complications of DM are further subdivided into microvascular (retinopathy, neuropathy, and nephropathy) and macrovascular complications (coronary heart disease [CHD], peripheral arterial disease [PAD], and cerebrovascular disease). Microvascular complications are DM-specific, whereas macrovascular complications have pathophysiologic features that are both shared with the general population and DM-specific. Nonvascular complications include infections, skin changes, and hearing loss. Some studies suggest that 2 DM increases the risk of dementia and impaired cognitive function.

The Diabetes Control and Complications Trial (DCCT) provided definitive proof that reduction in chronic hyperglycemia can prevent many complications of type 1 DM.

Figure 1. Rates of retinopathy progression for different HbA1c

The DCCT demonstrated that improvement of glycemic control reduced non-proliferative and proliferative retinopathy (47% reduction), albuminuria (39% reduction), clinical nephropathy (54% reduction), and neuropathy (60% reduction). The results of the DCCT predicted that individuals in the intensive DM management group would gain 7.7 additional years of vision, 5.8 additional years free from end-stage renal disease (ESRD), and 5.6 years free from lower extremity amputations. The 30-year follow-up data from the DCCT also show a continued reduction in retinopathy, nephropathy, and cardiovascular disease if patients were intensively treated. For example, individuals in the intensive therapy group had a 42–57% reduction in cardiovascular events (non-fatal myocardial infarction [MI], stroke, or death from a cardiovascular event) at a mean follow-up of 18 years, even though their subsequent glycemic control was the same as those in the conventional DM management group from years 6.5 to 17.

Microvascular complications include retinopathy, neuropathy, and nephropathy

COMPLICATION	TREATMENT
Retinopathy: non-proliferative and proliferative.	The most effective therapy for diabetic retinopathy is prevention. Intensive glycemic and blood pressure control will delay the development or slow the progression of retinopathy in individuals with either type 1 or type 2 DM. 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 DM specialist are inadequate to detect diabetic eye disease, which requires a dilated eye exam performed by an optometrist or ophthalmologist, and subsequent management by a retinal specialist for optimal care of these disorders.
Neuropathy: diffuse neuropathy (distal symmetrical polyneuropathy and/or autonomic neuropathy), mononeuropathy, and/or radiculopathy/polyradiculopathy.	Prevention of diabetic neuropathy is critical through improved glycemic control. Treatment of diabetic neuropathy is less than satisfactory. Lifestyle modifications (exercise, diet) has some efficacy in distal symmetric polyneuropathy in type 2 DM and hypertension and hypertriglyceridemia should be treated. Patients should be educated that loss of sensation in the foot increases the risk for ulceration and its sequelae and that prevention of such problems is paramount. If foot deformities are present, a podiatrist should be involved.
Nephropathy: albuminuria and declining renal function.	Screening for albuminuria should be performed annually in patients with type 1 DM for ≥5 years, in patients with type 2 DM, and during pregnancy. The optimal therapy for diabetic nephropathy is prevention by control of glycemia. Interventions effective in slowing progression of albuminuria include (1) improved glycemic control, (2) strict blood pressure control, and (3) administration of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB). Dyslipidemia should also be treated.

Macrovascular complications include CHD, cerebrovascular disease, and PAD

The Framingham Heart Study revealed a marked increase in PAD, coronary artery disease, MI, and congestive heart failure (CHF) (risk increase from one- to fivefold) in DM. In addition, the prognosis for individuals with DM who have coronary artery disease or MI is worse than for nondiabetics. CHD is more likely to involve multiple vessels in individuals with DM. In addition to CHD, cerebrovascular disease is increased in individuals with DM (threefold increase in stroke). Thus, after controlling for all known cardiovascular risk factors, type 2 DM still increases the cardiovascular death rate twofold in men and fourfold in women.

Treatment of coronary disease in the diabetic individual has substantial overlap with treatment of in individuals without DM. Revascularization procedures for CHD, including percutaneous coronary interventions (PCIs) and coronary artery bypass grafting (CABG), may be less efficacious in the diabetic individual. Initial success rates of PCI in diabetic individuals are similar to those in the nondiabetic population, but diabetic patients have higher rates of restenosis and lower long-term patency and survival rates in older studies. CABG plus optimal medical management likely has better outcomes than PCI for individuals with DM.

Aggressive cardiovascular risk modification in all individuals with DM and glycemic control should be individualized. In patients with known CHD and type 2 DM, an ACE inhibitor (or ARB), a statin, and aspirin should be considered. Beta blockers can be used in individuals with DM after MI. In patients with CHF, thiazolidinediones should not be used. However, metformin can be used in patients with stable CHF if the renal function is normal. Some newer glucose lowering therapies also have cardiovascular benefit, including sodium–glucose cotransporter 2 (SGLT2) inhibitors or glucagon-like peptide 1 receptor agonists (GLP-1 RA). Antiplatelet therapy reduces cardiovascular events in individuals with DM who have CHD and is recommended.

The optimal therapy for foot ulcers and amputations is prevention through identification of high-risk patients, education of the patient, and institution of measures to prevent ulceration. High-risk patients should be identified during the routine, annual foot examination performed on all patients with DM. Providers should consider screening for asymptomatic PAD in individuals >50 years of age who have DM and other risk factors using ankle-brachial index testing in high-risk individuals.

Footnotes:

ACE, angiotensin-converting enzyme; AGEs, angiotensin receptor blockers; advanced glycosylation end products; ARB, angiotensin receptor blockers; CABG, coronary artery
bypass grafting; CHD, coronary heart disease; DCCT, Diabetes Control and Complications Trial; DM, Diabetes mellitus; ESRD, end-stage renal disease; GLP-1 RA, glucagon-like
peptide 1 receptor agonists; MI, myocardial infarction; PAD, peripheral arterial disease; PCIs, percutaneous coronary interventions; SGLT-2, sodium–glucose cotransporter 2.

References:

Powers AC et al. Diabetes Mellitus: Complications. In: Jameson J et al. eds. Harrison's Principles of Internal Medicine, 20e. McGraw Hill; 2018.
https://accessmedicine.mhmedical.com/content.aspx?bookid=2129&sectionid=192288577. Accessed 26 Aug 2021.

Diabetes Mellitus