Diabetes Mellitus — Chronic Complications

This chapter covers the long-term microvascular and macrovascular complications of diabetes mellitus — diabetic neuropathy (peripheral and autonomic), nephropathy, retinopathy, cardiovascular disease, and foot complications — and the complication-directed screening, prevention, and pharmacotherapy specific to each. It is a companion to, and deliberately distinct from, the Diabetes Mellitus chapter, which covers diagnosis and glycemic-management pharmacotherapy; that foundation — individualized glycemic targets, blood pressure under 130/80 mmHg, and lipid management — remains the single most effective intervention for preventing or delaying every complication covered here, and is assumed rather than re-derived in this chapter.

Diabetes is as much a vascular and neurologic disease as a glycemic one: cardiovascular disease is the leading cause of death in people with diabetes, and complications are the primary driver of the excess morbidity, mortality, and reduced quality of life seen in this population.^[1] Several drug classes developed originally as glucose-lowering agents — SGLT2 inhibitors and GLP-1 receptor agonists chief among them — have since been shown to protect the kidney and cardiovascular system through mechanisms at least partly independent of glycemic control, and now form part of complication-specific pharmacotherapy in their own right rather than purely glycemic management.^[2]

Chronic complications are conventionally grouped as microvascular (retinopathy, nephropathy, and neuropathy — including its autonomic manifestations) and macrovascular (coronary artery disease, cerebrovascular disease, and peripheral arterial disease), though the diabetic foot sits at the intersection of both categories, arising from the combination of neuropathy and peripheral arterial disease together.

Autonomic neuropathy deserves specific attention because its manifestations are easy to miss without direct questioning: cardiovascular autonomic neuropathy can blunt the normal warning symptoms of myocardial ischemia (silent ischemia) and cause orthostatic hypotension; gastrointestinal autonomic neuropathy causes gastroparesis; genitourinary autonomic neuropathy contributes to erectile dysfunction; and sudomotor dysfunction causes abnormal sweating patterns. Ask about all of these directly rather than waiting for the patient to raise them.^[3]

Shared risk factors across complications

• Longer duration of diabetes.
• Higher lifetime A1c, and degree of glycemic control overall.
• Elevated blood pressure.
• Dyslipidemia.
• Obesity and physical inactivity.
• Smoking.

Retinopathy-specific

• Longer duration of diabetes.
• Elevated A1c.
• Elevated blood pressure.
• Dyslipidemia.
• Anemia.
• Pregnancy, in type 1 diabetes specifically.
• Proteinuria.
• Existing severe retinopathy — its own strongest predictor of further progression.

Nephropathy-specific

• Longer duration of diabetes.
• Lack of glycemic, blood pressure, or lipid control.
• Obesity.
• Smoking.

Neuropathy-specific

• Elevated blood glucose.
• Elevated triglycerides.
• Higher body mass index.
• Smoking.
• Hypertension.

Foot complication-specific

• Previous foot ulceration or amputation.
• Peripheral neuropathy (loss of protective sensation).
• Peripheral arterial disease.
• Structural foot deformity.
• Limited joint mobility.
• Any existing microvascular complication.
• Elevated A1c.
• Onychomycosis.

Chronic-complications screening schedule

Do not diagnose CKD from a urine ACR drawn during a transient cause of albuminuria — recent major exercise, a urinary tract infection, febrile illness, decompensated heart failure, menstruation, or an acute rise in glucose or blood pressure — repeat once the transient factor has resolved instead. A CKD diagnosis requires an eGFR under 60 mL/min/1.73m² and/or a urine ACR at or above 2 mg/mmol on at least 2 of 3 samples collected over a 3-month period.^[2][4]

Pregnancy accelerates retinopathy risk specifically in patients with pre-existing (type 1 or type 2) diabetes — evaluate before conception, in the first trimester, throughout pregnancy as needed, and within the first year postpartum; this accelerated schedule does not apply to gestational diabetes, which does not carry the same retinopathy risk.^[5]

Patients with a history of diabetic retinopathy who start an intensive glycemic regimen — frequent insulin injections, insulin pump therapy, or a GLP-1 receptor agonist — should have an eye exam before and shortly after the change: rapid improvement in glycemic control can transiently worsen retinopathy in the short term, independent of the specific drug class used.^[5]

History and examination

• Ask specifically about visual changes — patients often do not volunteer gradual vision loss unprompted.
• Ask about foot symptoms directly — numbness, burning, or a wound the patient may not have mentioned — since painless ulcers are easy to miss without direct questioning.
• Ask about erectile function and gastrointestinal symptoms (early satiety, bloating, unexplained erratic glucose control) directly rather than waiting for the patient to raise them — both are systematically underreported due to embarrassment or attribution to another cause.
• Check orthostatic vital signs (supine and standing blood pressure and heart rate) at least annually, and whenever autonomic neuropathy is suspected.

• Blood pressure under 130/80 mmHg in every patient with diabetes.
• LDL-C under 1.8 mmol/L (70 mg/dL) with statin ± ezetimibe/PCSK9 inhibitor in patients with established ASCVD; per current lipid-management targets otherwise.
• Urine ACR trending down or stable rather than progressively rising, with the annual rate of eGFR decline minimized to the smallest achievable.
• A1c per the individualized target already established in the companion Diabetes Mellitus chapter — glycemic control is foundational to preventing or delaying every complication in this chapter.
• Completion of the full annual complications-screening panel (retinopathy, nephropathy, neuropathy, foot) for every patient, every year it is due.
• Zero missed red-flag referrals — early identification and urgent referral prevents irreversible vision loss, limb loss, and renal failure.
• Complete smoking cessation.
• For gastroparesis: adequate symptom control and maintained nutritional status without need for enteral or parenteral nutrition.
• For erectile dysfunction: the ability to achieve an erection sufficient for satisfactory sexual activity, addressed as a routine part of diabetes care rather than left unasked.

Foot care

• Daily self-inspection of the feet, including between the toes, using a mirror if needed.
• Properly fitted footwear; avoid walking barefoot.
• Prompt professional care for any callus, corn, or nail problem rather than self-treatment with sharp instruments or over-the-counter corn removers.
• Professional offloading — therapeutic footwear, custom orthotics, or a total contact cast — for a high-risk or previously ulcerated foot.

Eye care

• Spectacle correction, magnification aids, and low-vision rehabilitation referral for patients with moderate visual loss.
• Report any new visual change to the care team promptly rather than waiting for the next scheduled eye exam.

Gastroparesis dietary measures

• Small, frequent meals rather than large meals.
• Reduce dietary fat and insoluble fibre, both of which slow gastric emptying further.
• A liquid or blenderized diet during symptom flares, since liquids empty by a different, less impaired mechanism than solids.
• Upright posture and gentle activity, such as walking, after meals.

Cardiovascular and general risk-factor measures

• Smoking cessation — one of the highest-yield interventions across every complication category in this chapter.
• Regular aerobic and resistance exercise, and a nutritionally balanced diet — see Diabetes Mellitus for the full lifestyle-intervention detail.

Erectile dysfunction — non-pharmacologic options

A vacuum erection device is a reasonable non-pharmacologic option, including as an adjunct to pharmacotherapy or when drug therapy is contraindicated or ineffective — see Male Sexual Dysfunction for full detail on device selection and technique counselling.

Pregnancy

Retinopathy can progress more rapidly during pregnancy in patients with pre-existing (type 1 or type 2) diabetes — screen before conception, in the first trimester, throughout pregnancy as needed, and within the first year postpartum; this accelerated schedule does not apply to gestational diabetes. Discontinue ACE inhibitors, ARBs, and statins before conception given teratogenic risk — see Diabetes Mellitus for the complete prepregnancy-planning checklist. Continue foot-care and neuropathy-screening as in the non-pregnant patient.

Breastfeeding

No specific restriction applies to the screening components of this chapter. Renoprotective and cardioprotective drug therapy — ACE inhibitors, ARBs, statins, SGLT2 inhibitors — is generally not initiated during breastfeeding given limited safety data; resume postpartum once breastfeeding has ended, or per specialist guidance if the clinical indication is urgent.

Pediatric

Retinopathy, nephropathy, and neuropathy screening in type 1 diabetes begins 5 years after diagnosis — retinopathy at or after age 15, nephropathy and neuropathy after 5 years' postpubertal duration — rather than at diagnosis, reflecting the very low complication risk in the pre-pubertal years.^[3] Foot complications are rare in children, but foot-care education should still begin early to build lifelong habits.

Renal impairment

Fenofibrate is contraindicated in severe renal impairment. Domperidone and erythromycin do not require dose adjustment for renal impairment specifically, but both carry QT-prolongation risk that renal disease can compound via electrolyte disturbance — check potassium and magnesium if either is a concern. SGLT2 inhibitors require no renal dose adjustment but should not be newly started below an eGFR of 20 mL/min/1.73m² — continue if already established and tolerated at a lower eGFR.^[6] ACE inhibitors and ARBs require creatinine/potassium monitoring rather than dose capping in most stages of CKD, though the dose may need reduction as renal function declines.

Hepatic impairment

Fenofibrate is contraindicated in significant hepatic impairment. Domperidone requires caution and dose reduction per the product monograph in hepatic impairment. Statins require closer transaminase monitoring in pre-existing liver disease.

Older adults

Autonomic neuropathy compounds fall risk in older adults through orthostatic hypotension — check orthostatic vital signs before intensifying any antihypertensive, and prefer agents less associated with orthostatic effects when autonomic neuropathy is present. Relax glycemic and, where clinically reasonable, blood pressure targets in frail older adults per the individualization approach in Diabetes Mellitus, while still pursuing complication screening and RAAS/SGLT2 renoprotection, both of which remain beneficial independent of glycemic target.

At every visit, ask directly about gastrointestinal symptoms and sexual function rather than waiting for the patient to raise them — both are systematically underreported.

1. Rising ACR or declining eGFR despite an ACE inhibitor/ARB and an SGLT2 inhibitor at maximum tolerated doses: confirm adherence and blood pressure control first, then refer to nephrology rather than adding a second RAAS-blocking agent.
2. Progressive retinopathy despite good glycemic and blood pressure control: this reflects the underlying disease trajectory more than a modifiable pharmacotherapy failure — confirm the ophthalmology follow-up interval is being met and consider a fenofibrate add-on if not already used.
3. Non-healing foot ulcer or recurrent ulceration despite offloading: refer for vascular assessment, since peripheral arterial disease is a common under-recognized contributor, and see Diabetic Foot Infections if infection is present.
4. Persistent gastroparesis symptoms despite an adequate prokinetic trial: reassess the diagnosis (rule out a new mechanical cause), optimize glycemic control, and refer to gastroenterology for further workup or device-based/interventional options.
5. Erectile dysfunction unresponsive to a PDE5 inhibitor: confirm correct use — timing, sufficient sexual stimulation, and an adequate dose actually trialed — before concluding failure, then refer per Male Sexual Dysfunction for second-line options.
6. Recurrent symptomatic orthostatic hypotension despite non-pharmacologic measures (hydration, gradual position changes, compression garments): refer for consideration of fludrocortisone or midodrine under specialist direction, and review the antihypertensive regimen for contributing agents.

• Combining an ACE inhibitor with an ARB — increases acute kidney injury and hyperkalemia risk without added renoprotective benefit.
• Stopping or never starting an SGLT2 inhibitor because of a reduced eGFR — the renoprotective benefit persists, and continuation is specifically recommended even as the glycemic effect diminishes, down to an eGFR of 20 mL/min/1.73m² and often beyond once already established.
• Treating the expected initial eGFR dip after starting an ACE inhibitor/ARB or SGLT2 inhibitor as an automatic reason to discontinue.
• Continuing metoclopramide beyond 12 weeks, or restarting repeated courses without a break — tardive dyskinesia risk rises with cumulative exposure, and is itself higher in people with diabetes.
• Starting domperidone in a patient over 60, or on another QT-prolonging drug, without an ECG/QT review.
• Missing a silent MI or severe orthostatic hypotension because cardiac autonomic neuropathy has blunted the expected warning symptoms — have a low threshold to investigate atypical or absent-symptom presentations in a patient with established autonomic neuropathy.
• Not asking directly about erectile function or gastrointestinal symptoms — both are underreported due to embarrassment or misattribution to another cause.
• Treating a diabetic foot ulcer without addressing offloading — antimicrobial therapy alone does not heal a wound that remains under continued pressure.
• Prescribing a PDE5 inhibitor without confirming the patient is not using any nitrate, including an as-needed sublingual product they may not think to mention.
• Assuming fenofibrate's retinopathy benefit is simply a byproduct of its lipid-lowering effect — the mechanism is distinct, so the add-on is appropriate even when lipids are already at target.
• Missing that ASA is indicated in diabetes for secondary prevention only, not routine primary prevention.

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

ACE inhibitors — nephropathy renoprotection

Start within any of hypertension, albuminuria, or established cardiovascular disease; never combine with an ARB.

ARBs — nephropathy renoprotection alternative

Use when an ACE inhibitor is not tolerated (e.g., cough); never combine with an ACE inhibitor.

SGLT2 inhibitors — nephropathy renoprotection

Initiate once eGFR is at least 20 mL/min/1.73m² and continue for renal protection even as eGFR declines below that level, unless not tolerated or kidney replacement therapy begins. Hold during acute illness, prolonged fasting, or major surgery. An initial reversible eGFR dip is expected and not itself a reason to stop.

GLP-1 receptor agonists — cardiorenal benefit

Chiefly reduces albuminuria; renal-outcomes evidence is less extensive than for the SGLT2 inhibitor class. See Diabetes Mellitus for the complete titration schedule.

Lipid-lowering therapy — cardiovascular and retinopathy-specific benefit

See Dyslipidemias for the complete statin-intensity selection algorithm.

Antiplatelet therapy — secondary cardiovascular prevention

Secondary prevention only in diabetes; not routine primary prevention without established ASCVD.

Gastroparesis — prokinetic agents

Correct hyperglycemia alongside prokinetic therapy — acute hyperglycemia itself slows gastric emptying and can blunt drug response.

Erectile dysfunction — PDE5 inhibitors and second-line therapy

See Male Sexual Dysfunction for the complete selection/dosing algorithm. Response may be reduced with longstanding diabetic autonomic neuropathy or vasculopathy. Absolutely contraindicated with any nitrate.