Diabetes Mellitus — Chronic Complications
Clinical Snapshot
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]
Recognize the Condition
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.
The 5 chronic-complication tracks in this chapter
Neuropathy
Peripheral sensorimotor neuropathy (numbness, pain, loss of protective sensation) and autonomic neuropathy affecting the cardiovascular, gastrointestinal, and genitourinary systems — gastroparesis and erectile dysfunction are both covered here as autonomic-neuropathy manifestations with real pharmacologic options.
Nephropathy
Progressive albuminuria and declining eGFR that can lead to end-stage kidney disease requiring dialysis or transplantation.
Retinopathy
Progressive retinal microvascular damage — the leading cause of new-onset blindness in the working-age population.
Cardiovascular disease
Accelerated atherosclerosis causing coronary artery disease, cerebrovascular disease, peripheral arterial disease, and heart failure — the leading cause of death in people with diabetes.
Foot complications
Ulceration and infection arising from the combination of neuropathy (loss of protective sensation) and peripheral arterial disease — the leading cause of non-traumatic lower-limb amputation.
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]
Risk Factors
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.
Red Flags & Refer
Escalate for same-day or urgent specialist assessment for any of the following:
- Rapidly progressive or sudden vision loss, new floaters, or a curtain/shadow across the visual field — urgent ophthalmology referral; do not wait for the next scheduled screening exam.
- Signs of a diabetic foot ulcer or infection — new skin breakdown, spreading redness/warmth, purulent drainage, malodour, or a wound that is not healing — same-day assessment; see Diabetic Foot Infections for the diagnostic and antimicrobial treatment approach once infection is confirmed.
- Signs of acute limb ischemia — a cold, pale, pulseless, or acutely painful foot — emergency vascular assessment.
- Rapidly declining renal function — a sharp or accelerating rise in creatinine, new or rapidly worsening proteinuria, or an eGFR fall well beyond the expected initial dip after starting an ACE inhibitor/ARB or SGLT2 inhibitor — urgent nephrology referral.
- Signs of autonomic neuropathy causing silent cardiac ischemia — new dyspnea, fatigue, or reduced exercise tolerance without classic chest pain in a patient with known or suspected cardiac autonomic neuropathy — treat as possible ischemia and investigate, since the expected warning symptom may be blunted or absent.
- Severe orthostatic hypotension — presyncope, syncope, or a fall associated with a significant postural blood pressure drop — same-day assessment and review the medication list for contributing agents.
- Severe, refractory vomiting from gastroparesis causing dehydration or an inability to maintain oral intake — same-day assessment; may need IV fluids or hospital-based management.
Assessment & Diagnosis
Chronic-complications screening schedule
| Complication | Who and when to start | Test | Repeat interval |
|---|---|---|---|
| Retinopathy | Type 2 diabetes: at diagnosis. Type 1 diabetes: annually beginning 5 years after diagnosis, at or after age 15. | Dilated eye exam (optometry/ophthalmology) or validated retinal photography | Type 2: every 1-2 years if normal, more often if retinopathy is found. Type 1: annually. |
| Nephropathy | Type 2 diabetes: at diagnosis. Type 1 diabetes: annually beginning 5 years after diagnosis. | Random urine ACR and serum creatinine (eGFR) | At least annually; more often once CKD is established. |
| Neuropathy | Type 2 diabetes: at diagnosis. Type 1 diabetes: annually beginning after 5 years' postpubertal duration. | 10-g monofilament and vibration sense at the dorsum of the great toe | Annually. |
| Foot | All patients with diabetes. | Visual inspection, pulses, deformity, and footwear review, informed by the neuropathy/PAD screening above | Annually; more often if high-risk. |
| Cardiovascular risk | All patients with diabetes. | Blood pressure at every visit; fasting lipid panel at diagnosis | Lipids annually if untreated, every 3-6 months once treated. |
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.
Treatment Targets
- 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.
Choose Initial Treatment
Diabetic nephropathy — RAAS blockade and SGLT2 inhibitor renoprotection
1st line start an ACE inhibitor or ARB — never both together — in any patient with diabetes and hypertension or albuminuria; the renoprotective benefit is not established in normotensive patients without albuminuria, so do not start RAAS blockade purely as prophylaxis in that group.[2]
1st line, added independent of RAAS blockade start an SGLT2 inhibitor (dapagliflozin, empagliflozin, or canagliflozin) in every adult with type 2 diabetes and CKD once eGFR is at least 20 mL/min/1.73m², regardless of current A1c — this is an organ-protection decision, not a glycemic one, and the drug should be continued even after its glucose-lowering effect has become negligible.[6]
Do not combine an ACE inhibitor with an ARB — dual RAAS blockade increases the risk of acute kidney injury and hyperkalemia without an added renoprotective benefit.[2]
Special situation a GLP-1 receptor agonist (dulaglutide, liraglutide, or subcutaneous semaglutide — see Diabetes Mellitus for full titration) can be added for its own renal benefit, chiefly a reduction in albuminuria, when further glycemic or weight benefit is also wanted, though its renal-outcomes evidence base is less extensive than the SGLT2 inhibitor class.[2]
Advise every patient of childbearing potential taking an ACE inhibitor or ARB to avoid pregnancy while on the drug, and to contact their care team promptly if pregnancy occurs, given the risk of fetal congenital malformation.
Cardiovascular risk reduction
1st line start a statin in every adult with diabetes who is 40 years of age or older, has established ASCVD, or is under 40 with diabetes duration over 15 years plus age over 30, a microvascular complication, or additional cardiovascular risk factors.[1]
Add-on for those not at LDL goal on a maximally tolerated statin ezetimibe first, then a PCSK9 inhibitor if LDL-C remains above target — see Dyslipidemias for the complete lipid-management algorithm.
Special situation, established retinopathy add fenofibrate to statin therapy specifically to slow retinopathy progression — this benefit is a distinct mechanism from, and additional to, its lipid-lowering effect, and applies even when lipids are already at target.[5]
Secondary prevention only low-dose ASA (81 mg once daily) for patients with established cardiovascular disease; clopidogrel 75 mg once daily if ASA is not tolerated.
Do not use ASA routinely for primary cardiovascular prevention in diabetes without established disease — the bleeding risk is not reliably offset by a cardiovascular benefit in this setting.[1]
Antihyperglycemic selection in adults with type 2 diabetes and established ASCVD, heart failure, or CKD, prioritize an SGLT2 inhibitor and/or GLP-1 receptor agonist with proven cardiorenal benefit as part of the glucose-lowering regimen — see Diabetes Mellitus for the complete drug-selection algorithm.[7]
Treat blood pressure to a target under 130/80 mmHg in every patient with diabetes — see Hypertension for the full antihypertensive algorithm; the ACE inhibitors/ARBs and SGLT2 inhibitors used here for renoprotection typically also contribute meaningfully to this target.
Diabetic peripheral neuropathy
Foundational to every patient optimize glycemic control as part of the neuropathy-prevention and -management plan — this is the only intervention shown to reduce the onset and progression of neuropathy itself, independent of pain control.[3]
For symptomatic painful diabetic peripheral neuropathy, gabapentin, pregabalin, duloxetine, and amitriptyline all have the strongest evidence base in this specific population and are reasonable initial choices — see Neuropathic Pain for the complete dosing, titration, and agent-selection guidance; this chapter's role is diabetes-specific screening and the broader complications context, not re-deriving that dosing.
Diabetic retinopathy
Primary prevention optimal glycemic control and blood pressure control under 130/80 mmHg are the most effective interventions for reducing the development and progression of retinopathy — pharmacotherapy for established retinopathy itself (anti-VEGF injection, laser photocoagulation, or vitreoretinal surgery) is ophthalmology-directed and not administered by a community pharmacist; the pharmacist's role is ensuring the systemic risk factors above are controlled and screening intervals are met.[8]
Diabetic foot complications
Prevention, every patient perform or arrange an annual foot exam and stratify risk (see Clinical Decision Algorithm) to set the follow-up interval and referral threshold — routine preventive foot care is the highest-yield intervention for avoiding ulceration and amputation.[9]
Active ulcer or suspected infection refer the same day — see Diabetic Foot Infections for the complete diagnostic and antimicrobial treatment approach; this chapter's foot-complications content is limited to the preventive, screening, and referral-timing angle.
Gastroparesis
1st line metoclopramide 10 mg PO before meals and at bedtime, for a course under 12 weeks given its tardive dyskinesia risk — a risk that is itself higher in patients with diabetes, so avoid extending or repeating courses without a clear break.[10]
Alternative, avoids extrapyramidal/tardive dyskinesia risk domperidone 10 mg PO three times daily (maximum 30 mg/day), with baseline ECG/QT review — avoid in patients over 60 or with a QT-prolonging drug or condition.
Special situation, short-term add-on low-dose erythromycin when metoclopramide/domperidone are inadequate or contraindicated — expect a rapid loss of effect, within days to weeks, from motilin-receptor downregulation, so use short, defined courses rather than continuous therapy.[10]
Correct hyperglycemia as part of every gastroparesis treatment plan — acute hyperglycemia itself slows gastric emptying and can blunt the response to prokinetic therapy.
Erectile dysfunction
1st line a PDE5 inhibitor (sildenafil, tadalafil, or vardenafil) — see Male Sexual Dysfunction for full dosing and selection guidance; the diabetes-specific nuance is that longstanding autonomic neuropathy and vascular disease can blunt response compared to non-diabetic patients, so set expectations accordingly and do not conclude the class has failed after a single suboptimal dose.[11]
Absolute contraindication any PDE5 inhibitor with concurrent nitrate use, including an as-needed sublingual nitroglycerin product — the combination causes severe, potentially fatal hypotension; confirm nitrate use specifically before prescribing, since patients may not think to mention an as-needed product.
2nd line, after PDE5 inhibitor failure intracavernosal alprostadil, particularly relevant in diabetes given the vasculogenic component that is frequently present alongside the neuropathic one.[11]
Non-Pharmacologic Treatment
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.
Special Populations
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.
Monitoring & Follow-Up
| What to check | Frequency | Action if abnormal |
|---|---|---|
| Serum creatinine/eGFR and potassium | Baseline and 1-2 weeks after starting or increasing an ACE inhibitor or ARB; at least annually thereafter | A creatinine rise up to about 30% from baseline, or mild hyperkalemia, is expected and not itself a reason to stop — investigate and consider dose reduction or specialist input for a larger or progressive change. |
| eGFR | Before starting an SGLT2 inhibitor, and periodically thereafter based on volume status, blood pressure, other medications, and illness | An initial reversible dip is expected; hold during acute illness, prolonged fasting, or major surgery. |
| Urine ACR | At least annually once CKD is established, more often per nephrology guidance | Rising or non-improving ACR despite RAAS blockade and an SGLT2 inhibitor: confirm adherence and blood pressure control, then consider nephrology referral. |
| Dilated eye exam | Per the screening schedule in Assessment & Diagnosis | Any new visual change or exam finding: ophthalmology referral per severity. |
| 10-g monofilament and vibration testing | Annually | Loss of protective sensation: escalate the foot-risk category and referral interval. |
| Foot exam | Annually; more often if high-risk | New deformity, callus, or skin breakdown: foot-care specialist referral. |
| Orthostatic vital signs | Annually, and whenever autonomic neuropathy is suspected or an antihypertensive is intensified | Symptomatic orthostatic drop: reassess the antihypertensive regimen, and try non-pharmacologic measures first. |
| Fasting lipid panel | At diagnosis, then annually if untreated or every 3-6 months once lipid-lowering treatment starts | Not at LDL target on a maximally tolerated statin: add ezetimibe, then a PCSK9 inhibitor. |
At every visit, ask directly about gastrointestinal symptoms and sexual function rather than waiting for the patient to raise them — both are systematically underreported.
Common Errors to Avoid
- 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.
Clinical Decision Algorithm
Drug Tables
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Ramipril | Initial: 1.25-2.5 mg PO once daily Target (renoprotection): 10 mg PO once daily | Cough, hyperkalemia, hypotension, rare angioedema | Hyperkalemia risk with potassium-sparing diuretics/spironolactone/NSAIDs; avoid with lithium | Check creatinine and potassium at baseline and 1-2 weeks after starting or increasing the dose. |
| Lisinopril | Initial: 2.5-5 mg PO once daily Target: 20-40 mg PO once daily | Cough, hyperkalemia, hypotension, rare angioedema | Hyperkalemia risk with potassium-sparing diuretics/spironolactone/NSAIDs; avoid with lithium | |
| Perindopril erbumine | Initial: 2 mg PO once daily Target: 8 mg PO once daily | Cough, hyperkalemia, hypotension, rare angioedema | Hyperkalemia risk with potassium-sparing diuretics/spironolactone/NSAIDs; avoid with lithium |
ARBs — nephropathy renoprotection alternative
Use when an ACE inhibitor is not tolerated (e.g., cough); never combine with an ACE inhibitor.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Losartan | Initial: 50 mg PO once daily Target: 100 mg PO once daily | Hyperkalemia, hypotension, dizziness | Hyperkalemia risk with potassium-sparing diuretics/spironolactone | |
| Candesartan cilexetil | Initial: 8 mg PO once daily Target: 32 mg PO once daily | Hyperkalemia, hypotension | Hyperkalemia risk with potassium-sparing diuretics/spironolactone | |
| Valsartan | Initial: 80 mg PO once daily Target: 160-320 mg PO once daily | Hyperkalemia, hypotension | Hyperkalemia risk with potassium-sparing diuretics/spironolactone |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Dapagliflozin | Adults: 10 mg PO once daily | Genital mycotic infection, volume depletion/hypotension, rare euglycemic DKA | Loop diuretics increase hypotension risk | |
| Empagliflozin | Adults: 10-25 mg PO once daily | Genital mycotic infection, volume depletion/hypotension, rare euglycemic DKA | Loop diuretics increase hypotension risk | |
| Canagliflozin | Adults: 100-300 mg PO once daily | Genital mycotic infection, volume depletion/hypotension, hyperkalemia, rare euglycemic DKA | Strong enzyme inducers (rifampin, phenytoin, carbamazepine) reduce plasma levels; loop diuretics increase hypotension risk |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Subcutaneous semaglutide | Initial: 0.25 mg SC once weekly x4 weeks Titration: 0.5 mg SC once weekly, may increase to 1 mg weekly after a further 4 weeks | Nausea, vomiting, diarrhea, rare acute pancreatitis | May reduce the absorption rate of some oral medications | |
| Dulaglutide | Initial: 0.75 mg SC once weekly Maintenance: Typically increased to 1.5 mg SC once weekly | Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis | May reduce the absorption rate of some oral medications | |
| Liraglutide | Initial: 0.6 mg SC once daily Maintenance: Increase to 1.2-1.8 mg SC once daily | Nausea, vomiting, diarrhea, injection-site reactions, rare acute pancreatitis | May reduce the absorption rate of some oral medications |
Lipid-lowering therapy — cardiovascular and retinopathy-specific benefit
See Dyslipidemias for the complete statin-intensity selection algorithm.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Atorvastatin | Adults: 10-80 mg PO once daily, intensity per cardiovascular risk category | Myalgia, transaminase elevation | Strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole) increase levels | |
| Rosuvastatin | Adults: 5-40 mg PO once daily, intensity per cardiovascular risk category | Myalgia, transaminase elevation | Fewer CYP3A4 interactions than atorvastatin | |
| Ezetimibe | Adults: 10 mg PO once daily | Myalgia (mild), GI upset | None significant | Add if LDL remains above target on a maximally tolerated statin. |
| Fenofibrate | Adults: 145-200 mg PO once daily, depending on formulation | Myopathy risk increased when combined with a statin, transaminase elevation, rare pancreatitis, reversible creatinine rise | Increased myopathy risk with statins; potentiates warfarin | Added specifically to slow diabetic retinopathy progression in patients with existing retinopathy, independent of and additional to its lipid effect. Contraindicated in severe renal or hepatic impairment. |
Antiplatelet therapy — secondary cardiovascular prevention
Secondary prevention only in diabetes; not routine primary prevention without established ASCVD.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Acetylsalicylic acid | Adults: 81 mg PO once daily | GI upset, bleeding | Increased bleeding with other antiplatelet/anticoagulant agents | |
| Clopidogrel | Adults: 75 mg PO once daily | Bleeding, rash | Increased bleeding with other antiplatelet/anticoagulant agents | Use in place of ASA, not as a routine add-on, when ASA is not tolerated. |
Gastroparesis — prokinetic agents
Correct hyperglycemia alongside prokinetic therapy — acute hyperglycemia itself slows gastric emptying and can blunt drug response.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Metoclopramide | Adults: 10 mg PO/IV/IM before meals and at bedtime (up to 4 times daily); maximum 40 mg/day; maximum 12 weeks of therapy | Extrapyramidal symptoms, tardive dyskinesia (boxed warning — risk rises with cumulative dose and duration), sedation, restlessness | Additive sedation/extrapyramidal effects with antipsychotics; avoid with drugs that lower seizure threshold | Diabetes is itself an independent risk factor for tardive dyskinesia with this drug — do not exceed the 12-week limit or restart repeated courses without a clear break. |
| Domperidone | Adults: 10 mg PO three times daily before meals; maximum 30 mg/day | QT interval prolongation, rare ventricular arrhythmia/sudden cardiac death, hyperprolactinemia | Avoid with other QT-prolonging drugs and strong CYP3A4 inhibitors, which raise domperidone levels | Avoid in patients over 60 years of age or with a QT-prolonging condition/drug; obtain a baseline ECG in higher-risk patients per Health Canada's current dosing guidance. |
| Erythromycin (low-dose prokinetic) | Adults: 125-250 mg PO three times daily, 30 minutes before meals, in short courses | QT prolongation, GI upset (can itself mimic worsening gastroparesis), rare hepatotoxicity | Strong CYP3A4 inhibitor with numerous interactions (e.g., increases levels of some statins, warfarin, carbamazepine); avoid with other QT-prolonging drugs | Effect diminishes rapidly, within days to weeks, from motilin-receptor downregulation — use short, defined courses or a scheduled drug-holiday pattern rather than continuous therapy. |
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.
| Drug | Dosage | Adverse effects | Drug interactions | Comments |
|---|---|---|---|---|
| Sildenafil | Adults: 25-100 mg PO approximately 1 hour before sexual activity (range 30 minutes-4 hours), maximum once daily | Headache, flushing, dyspepsia, visual disturbance (blue-tinged vision), hypotension | Contraindicated with any nitrate; strong CYP3A4 inhibitors raise levels — reduce dose | An adequate trial means multiple attempts at an adequate dose with sufficient sexual stimulation before concluding failure. |
| Tadalafil | On-demand: 10 mg PO before sexual activity (range 5-20 mg), effective up to 36 hours Continuous dosing: 2.5-5 mg PO once daily | Headache, dyspepsia, back pain, myalgia | Contraindicated with any nitrate; strong CYP3A4 inhibitors raise levels | Longer half-life means a longer required washout period before nitrate use than for sildenafil/vardenafil. |
| Vardenafil | Adults: 10 mg PO approximately 1 hour before sexual activity (range 5-20 mg) | Headache, flushing, dyspepsia, hypotension | Contraindicated with any nitrate; strong CYP3A4 inhibitors raise levels | |
| Alprostadil | Adults: Intracavernosal injection, individualized starting dose established via in-office titration | Penile pain, priapism/prolonged erection, corporal fibrosis with repeated use, hypotension | None significant via the intracavernosal route | 2nd line after PDE5 inhibitor failure or contraindication — a common scenario in diabetes given the frequent combined vasculogenic/neurogenic etiology; requires initial in-office dose-finding and technique teaching. |
References
- Cardiovascular Protection in People With Diabetes — Diabetes Canada Clinical Practice Guidelines Expert Committee (Stone JA, Houlden RL, Lin P, et al.). Can J Diabetes 2018;42(Suppl 1):S162-S169
- Chronic Kidney Disease in Diabetes: A Clinical Practice Guideline — Diabetes Canada Clinical Practice Guidelines Steering Committee (Tobe SW, Bajaj HS, Tangri N, et al.). Can J Diabetes 2025;49(2):73-86.e14
- Neuropathy — Diabetes Canada Clinical Practice Guidelines Expert Committee (Bril V, Breiner A, Perkins BA, Zochodne D). Can J Diabetes 2018;42(Suppl 1):S217-S221
- 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 — American Diabetes Association Professional Practice Committee. Diabetes Care 2026;49(Suppl 1):S246-S260
- Retinopathy — Diabetes Canada Clinical Practice Guidelines Expert Committee (Altomare F, Kherani A, Lovshin J). Can J Diabetes 2018;42(Suppl 1):S210-S216
- KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease — Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (Stevens PE, et al.). Kidney Int 2024;105(4 Suppl):S117-S314
- Pharmacologic Glycemic Management of Type 2 Diabetes in Adults — 2024 Update — Diabetes Canada Clinical Practice Guidelines Expert Working Group (Shah BR, Bajaj HS, Butalia S, et al.). Can J Diabetes 2024;48(7):415-424
- 12. Retinopathy, Neuropathy, and Foot Care: Standards of Care in Diabetes—2026 — American Diabetes Association Professional Practice Committee. Diabetes Care 2026;49(Suppl 1):S261-S276
- Foot Care — Diabetes Canada Clinical Practice Guidelines Expert Committee (Embil JM, Albalawi Z, Bowering K, Trepman E). Can J Diabetes 2018;42(Suppl 1):S222-S227
- AGA Clinical Practice Guideline on Management of Gastroparesis — American Gastroenterological Association (Staller K, Parkman HP, Greer KB, et al.). Gastroenterology 2025;169(5):828-861
- Erectile Dysfunction: AUA Guideline — American Urological Association (Burnett AL, Nehra A, Breau RH, et al.). J Urol 2018;200(3):633-641
Professional reference only. Apply clinical judgment and verify patient-specific decisions against current authoritative guidance and product information.