Depression

Elevated depressive symptoms and depressive disorders affect 25% of patients with type 2 diabetes,²⁵ and increase the risks of hyperglycemia, insulin resistance, and micro- and macrovascular complications.²⁶

Providers should consider screening diabetes patients for depressive symptoms annually, and whenever there are major changes in medical status (eg, new complications, treatment intensification, etc).²⁷

Depression screening can be done with the PHQ-2. For example: “Over the last 2 weeks, how often have you been bothered by any of the following problems?”.

1. “Little interest or pleasure in doing usual things?”
2. “Feeling down, depressed or hopeless?”

Patients who respond “yes” to either question should be further evaluated using the full PHQ-9 to determine whether they meet criteria for a depressive disorder. See UMHS clinical guideline on depression for more information on the PHQ-9.

Both psychotherapy and antidepressant medication are moderately effective for depression, and cognitive behavior therapy (CBT) has additional benefits for glycemic control.²⁸

If PHQ-9 total ≥10: Patients should be treated for depression with pharmacotherapy and/or referral to a behavioral health specialist for cognitive behavioral therapy (CBT), or antidepressant management. See UMHS clinical guideline on depression for full details on depression treatment.

PHQ-9 totals of 5-9: Consider depression treatment, counseling/psychotherapy, or watchful waiting, and repeat PHQ-9 at follow-up.

Disordered eating behaviors

Consider screening for disordered/disrupted eating or omission of insulin doses when hyperglycemia is unexplained. Patients with diagnosable eating disorder can be referred to a specialty behavioral health provider.

Diabetes-related distress

Diabetes distress refers to significant negative psychological reactions to having diabetes. This is distinct from depressive and anxiety disorders, affects up to 45% of patients, and is linked with poor glycemic control, medication non-adherence, and poor dietary and exercise behaviors.

Routinely monitor for diabetes distress, especially when treatment targets are not met and/or at the onset of diabetes complications.²⁷

Screening can be accomplished with the Diabetes Distress Scale – 2 (DDS-2).²⁹ Patients rate how much each problem has distressed or bothered them over the past month using the following 6-point scale: 1-Not a problem, 2-Slight problem, 3-Moderate problem, 4-Somewhat serious problem, 5-Serious problem, 6-Very serious problem.

1. Feeling overwhelmed by the demands of living with diabetes.
2. Feeling that I am often failing with the prescribed diabetes regimen.

A total score of 6 or more indicates significant diabetes distress and is an indication for intervention.

Patients who screen positive for diabetes distress should first be offered diabetes education to address the areas of self-management that are most relevant to their personal concerns and health outcomes. Those who do not respond to education should be referred to a specialty behavioral health provider familiar with diabetes self-management.

Practical/logistical issues

One of the most common barriers to adherence is the ability to obtain testing supplies and medications by both patients and physicians. There are several practical considerations.

Diabetes medications are frequently the target of the insurance companies’ ever-changing formularies, resulting in unexpected changes to patients’ out-of-pocket expenses. Physicians often experience requests for a medication change (within and outside of drug class) and prior authorizations requests. Increased medication expenses often lead to patient non-adherence and/or financial hardship. Delays may occur in obtaining crucial medications while prescriptions are changed and/or prior authorizations are acquired. In order to minimize disruptions, ACUs should have processes and procedures in place to facilitate physicians, nurses, pharmacists, and other team members to identify financial barriers to medication adherence, update nursing protocols regularly regarding pre-approved medication substitutions, and employ an efficient and effective medication prior authorization procedure. (Nursing protocols can be found at http://www.med.umich.edu/i/acs/nursing/standingorders/standingorders_protocols.html)

Ordering diabetes testing supplies often represents an even greater challenge. Physicians are often not familiar with the pros and cons of various devices, and insurers often limit the available options, making writing specific prescriptions challenging. If a specific meter known for its accuracy is prescribed it may not be covered by insurance, unintentionally delaying care. If the meter choice is made by the DME, or pharmacy, the result may be a meter that is only within an acceptable margin of error 75% of the time. For a recent study of glucometers, please see: https://www.diabetestechnology.org/surveillance.shtml.

Most medications are covered by a patient’s pharmacy benefit, however 80% of insurance plans categorize diabetes testing supplies, including continuous glucose meters, and some insulin delivery devices (insulin pumps) as Durable Medical Equipment (DME). Like medications, the brand and type of diabetes testing supplies available under a plan changes from year-to-year, but there is the additional provision of where to obtain them (specific DMEs or Pharmacies). This frequently leads to patients presenting at a pharmacy with a prescription for test strips, only to be told that test strips are not covered under their pharmacy benefit plan; and failing to be told that they are covered under their DME coverage. It is a Michigan law that insurers cover testing supplies. (https://www.michigan.gov/difs/0,5269,7-303-12902_35510_92612_92613_92614_92867-497018--,00.html)

Most insurers, including Medicare, require more than a testing supply prescription for reimbursement. Most DME companies and some pharmacies fax or email staff questionnaires, or Certificates of Medical Necessity (CMNs) for completion. In an effort to eliminate unnecessary, duplicative paper work, Michigan Medicine’s Adult Diabetes Education program designed order sets in the Meds and Orders tab in MiChart. When signed, these are automatically sent to the selected DME company. Pharmacies require separate prescriptions for each item and a follow up fax for CMNs. The Adult Diabetes Education program continues to work with the remaining local and national DMEs and local pharmacies, in conjunction with the Endocrine Society and other academic institutions, to achieve greater acceptance of our electronic ordering of diabetes supplies.

There are two order sets in Michart. Diabetes DME- Testing supplies, (available for any provider to use to order glucometers, test strips, and lancets from a DME) and Diabetes DME – insulin pump and CGM supplies, (which is restricted to adult and pediatric diabetes education.) This restriction is due to the need to understand the various insurers requirements to obtain these devices and supplies. Please place a referral to diabetes education if you are wish to order an insulin pump or CGM for your patient.

Smoking cessation: Tobacco and E-Cigarettes

Smoking and diabetes are synergistic risk factors for the development of atherosclerotic cardiovascular disease, microvascular disease, premature death and worsen glycemic control. Smoking is a risk factor for type 2 diabetes. Centers for Disease Control and Prevention recommends against the use of e-cigarettes either as a tobacco cessation product or as a recreational drug in light of deaths related to e-cigarettes. People with diabetes should be counseled regarding these risks, and all possible measures should be used to encourage patients to stop smoking. This includes enrollment in formal tobacco cessation programs and use of alternative nicotine delivery systems or pharmacologic therapies. Pharmacological therapy in addition to counseling is more effective than either treatment alone.

Glycemic Control

Hemoglobin A1c is the most commonly accepted measurement of long-term glycemic control, although factors such as hemolytic anemia and hemoglobinopathies can cause A1c measurement to be inaccurate.

Targets for glycemic control

Targets for therapy of Type 2 diabetes have been evaluated in four large clinical trials: UK Prospective Diabetes Study (UKPDS), Action to Control Cardiovascular Risk in Diabetes study (ACCORD), Action in Diabetes and Vascular Disease Controlled Evaluation (ADVANCE) and The VA Diabetes Trial (VADT). An overview of each of these four trials is included in Appendix A. The intensive control group in each of the four trials achieved A1c levels ≤7.0. All four trials demonstrated reduction in microvascular outcomes with intensive glycemic control. All except ACCORD demonstrated reduction in macrovascular outcomes with intensive glycemic control. Therefore, many patients will benefit from a hemoglobin A1c goal less than 7%.

Conversely, a strict A1c goal of <7% may not be appropriate for many patients. ACCORD demonstrated an increase in macrovascular outcomes with intensive glycemic control. A 2019 metanalysis demonstrated that patients with pre-existing cardiovascular disease do not derive macrovascular benefit from strict control.⁴⁵ Additionally, much of the microvascular benefit demonstrated by the four key trials derives from reduction in surrogate endpoints that may not be clinically important to patients such as microalbuminuria and fundoscopic appearance of early asymptomatic retinopathy.

Therefore, A1c targets should be individualized based on patient-specific factors. A1c targets should be discussed with patients. Providers should weigh patient-specific factors when considering glycemic goals (Table 4). Two important concepts that need consideration when selecting an A1c goal are 1. it takes years for symptomatic benefits to become apparent and 2. hypoglycemia is a potent predictor of mortality. Therefore, a number of factors may modify target levels. Factors that increase risk of hypoglycemia and its consequences include history of cardiovascular disease, previous history of hypoglycemia, hypoglycemia unawareness, and functional and/or cognitive limitations. Factors that limit life expectancy such as severe advanced comorbidities (advanced cancers, advanced heart failure) will limit the benefit of strict control. Furthermore, the burden, cost, and risk of the regimen needed to achieve a goal should also be considered.

Home Glucose Monitoring

Historically, evidence to support home blood glucose monitoring using finger stick glucose testing in type 2 diabetes treated with oral agents has been unconvincing. In addition to the fact that testing alone does not change glycemia, many patients find that finger sticks are painful, and thus is a common barrier to glucose self-monitoring.

More recently trials of continuous glucose monitoring (CGM), paired with behavioral coaching to help patients identify effective strategies for improving glycemia, have shown positive results.⁴⁶ CGM provides patients with real time feedback about the carbohydrate load in their diet and about episodes of hypoglycemia. Newer technologies including low cost and user friendly CGM such as the Abbott Freestyle Libre^® and the Dexcom G6^® do not require finger sticks and provide more detailed glucose feedback, including glucose levels during sleep. CGM is increasingly being used in patients struggling to control their type 2 diabetes. Medicare insures CGM for people with Type 2 Diabetes who test 4 times a day. Monitoring with these devices is less expensive than covering lancets and test strips. As the cost of CGM continues to decrease, finger stick glucose testing will be replaced by CGM for most patients with type 2 diabetes.

CGM also provides summary measures including percent time in range, percent time above range and percent time below range. Typically, the recommended range is 70 to 180 mg/dL but this can be adjusted for patient specific factors in most CGM devices. A target of 70% time in range and no more than 4 % time below range, allowing some time for post-prandial glucose over 140 mg/dL has been recommended, but the evidence base for this recommendation is limited.

Medications that increase blood sugar

Hyperglycemia is clinically defined as glucose greater than 180 mg/dL for more than two hours. Medications commonly contributing to elevated blood glucose or hyperglycemia include atypical antipsychotics, corticosteroids, calcineurin inhibitors (cyclosporine, sirolimus, tacrolmus), and protease inhibitors. Corticosteroids are a very common cause of hyperglycemia in patients with or without diabetes because they blunt the action of insulin and promote hepatic gluconeogenesis. Clore and Thurby-Hay recommend using NPH insulin for treating glucocorticoid-induced hyperglycemia or basal/prandial insulin can be used as well.

For atypical antipsychotics, second generation antipsychotics may increase risk of hyperglycemia or type 2 diabetes – particularly olanzapine and clozapine whereas ziprasidone (Geodon) and aripirazole (Abilify) have the lowest risk. Newer atypical antipsychotics such as aspenapine, iloperidone, paliperidone and lurasidone also have lower metabolic risk similar to aripiprazole and ziprasidone.

Calcineurin inhibitors are often used to avoid allograft rejection in transplant which can result in post-transplant diabetes. The incidence of post-transplants diabetes is ~24% within 3 years post-transplant. These medications inhibit pancreatic islet beta cell expansion promoted by calcineurin.

Protease inhibitors are essential in the treatment of HIV and AIDS. They are thought to cause decrease in insulin sensitivity thereby resulting in insulin-resistance associated hyperglycemia. This occurs in 3-17% of patients.

Other agents that increase blood glucose include antibiotics specifically fluroquinolones (Gatifloxacin and Levofloxacin), beta blockers, statins, and thiazide diuretics. Beta blockers like atenolol, metoprolol and propranolol elevate blood glucose level by impairing release of insulin from pancreatic beta-cells. Carvedilol and nebivolol have not been associated with development of hyperglycemia or new-onset diabetes. For thiazides, like hydrochlorothiazide patients may not experience elevated levels for weeks (or not at all) if doses are kept low (12.5-25mg). Lastly, for statins, FDA drug safety announcement reported an increase in blood glucose and risk of diabetes with statins (JUPITER and PROVE-IT TIMI 22 trial) but that cardiovascular benefits outweighed risk of not using statins in patients with diabetes.

Vigilant monitoring of blood glucose should be done for patients on these medications irrespective of previous diabetes diagnosis. Use of these drugs are not contraindicated and clinical judgement while evaluating benefits versus risk of the use of these medications is recommended.

Hypoglycemia

Hypoglycemia is linked with increased risk of mortality thus outweighing the potential benefits on microvascular complications in some patients. It is also a marker of high absolute risk of cardiovascular events. Findings from ACCORD, ADVANCE and VADT trials caution aggressive approach in achieving glycemic targets in high-risk patients and recommends individualization of glycemic targets based on patient factors, comorbidity and life expectancy. Of note, these studies pre-date the GLP1-RA and SGLT2i drug classes where cardiovascular and renal benefits are seen.

Risk factors that increase treatment-associated hypoglycemia include: use of insulin or secretagogues, impaired kidney or hepatic function, longer duration of diabetes, frailty and elderly patients, declined cognitive function, hypoglycemia unawareness, alcohol use, polypharmacy (ie, beta blocker).

While healthy, non-diabetic individuals can be asymptomatic with fasting serum glucose as low as 45 mg/dL without concerns, in patients with Type 2 diabetes who are taking medications that increases the risk for hypoglycemia (especially insulin and sulfonylureas), the definition of hypoglycemia is glucose <70 mg/dL (3.9 mmol/L). Some patients with diabetes who desire very tight control (ie, pregnant women) may tolerate and possibly benefit from lower glucose levels without adverse effects, but the risk of serious hypoglycemia increases with tighter control. There are three levels of hypoglycemia. Level 1 is glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L). Level 2 is glucose <54 mg/dL (3.0 mmol/L) and level 3 is defined as a severe event marked by altered physical and/or mental status requiring assistance in the treatment of hypoglycemia. There are patients who have hypoglycemia unawareness which is defined as level 2 hypoglycemia without any symptoms.

Symptoms of hypoglycemia include but are not limited to: irritability, sweating, shakiness, confusion, lightheadedness, hunger, and dizziness. Level 3 hypoglycemia can result in seizures, loss of consciousness, coma, or death. A large trial suggested that a history of level 3 hypoglycemia was associated with greater risk of dementia. Symptoms may vary between patients; therefore, education and assessment of symptoms of hypoglycemia is important.

The best approach for treatment is fast-acting glucose or carbohydrate (15-20 grams) in patients who are conscious with blood glucose <70 mg/dL (3.9 mmol/L). Pure glucose is preferred versus the total carbohydrate content of the food as it results in quicker response. Any form of glucose is acceptable. Added fat and protein may blunt glucose and increase insulin response thus prolonging acute glucose response. Avoid carbohydrate sources high in protein or fat to treat hypoglycemia. Fifteen minutes after the glucose consumption, check glucose. If blood glucose is still <70 mg/dL (3.9 mmol/L), repeat with 15-20 grams of glucose. Once glucose returns to normal, then patient should have a meal or snack to prevent the recurrence of hypoglycemia.

Glucagon should be prescribed to patients who are at risk of level 2 and 3 hypoglycemia. Glucagon is indicated when patients are unable or unwilling to consume carbohydrates by mouth. Glucagon administration teaching should be given to caregivers, school staff, or family members.

Hypoglycemia unawareness, severe (one or more level 3 hypoglycemia) or frequent hypoglycemia is an indication for modification of treatment regimen and glycemic targets. In addition, consider prescribing a continuous glucose monitor to detect and alarm for dangerously low glucose. Beta blockers can inhibit symptoms of hypoglycemia such as tachycardia and flight or fight symptoms except sweating.

Assessment of cause of hypoglycemia and education on how to prevent and treat hypoglycemia is recommended. Patient education on situations (ie, lifestyle including diet and exercise) and medications that can increase risk of hypoglycemia should be provided.

Use of CGM technology can be a useful tool in reducing time in hypoglycemic range in people with hypoglycemia unawareness.

Hypertension

Hypertension (HTN) is the predominant predictor of adverse events in patients with type 2 diabetes. Treatment of blood pressure reduces risks of major cardiovascular events such as myocardial infarction, stroke, or cardiovascular death, and also reduces the risk of microvascular outcomes such as visual loss, photo-coagulation for retinopathy, and the development of end-stage renal disease. Treatment of HTN in patients with type 2 diabetes should be a high priority for clinicians.

The majority of patients with diabetes and HTN have essential hypertension. However, it is important to identify secondary causes of HTN such as renal artery stenosis, primary hyperaldosteronism, pheochromocytoma, Cushing’s disease, and oral contraceptive use in patients who remain refractory to therapy, or who have clinical syndromes suggestive of these conditions.

Blood pressure target. The target BP depends on the presence of other risk factors.

Without risk: 140/90 mmHg with no ASCVD, ASCVD 10-year risk < 10%, and no DKD. (ASCVD risk is based on the ACC/AHA pooled cohort ASCVD risk calculator. Diabetes is already considered in calculating ASCVD risk.).

With ASCVD, ASCVD 10-year risk ≥ 10%, or DKD:

• - <130/80 mmHg if without risk for hypotension (eg, without: orthostatic hypotension, heart failure, older age).
• - Consider <140/90 mmHg if risk for hypotension.

Both age and diabetes are important factors in the ACC/AHA ASCVD risk calculator, resulting in a BP target of <130/80 mmHG for most patients with diabetes. Having diabetes essentially doubles an individual’s risk that results from other factors. Even with normal values for blood pressure, cholesterol, and a history of no smoking, with diabetes men age ≥ 55 years and women age ≥ 65 years will have a 10 -year ASCVD risk >10%. Many middle-age adults and some younger adults with diabetes and with other risk factors for ASCVD will have a calculated 10-year ASCVD risk >10%.

For patients at risk for hypotension (eg, orthostatic hypotension, heart failure, older age), consider a treatment target of <140 mmHg systolic and <90 mmHg diastolic blood pressure. The BP target is higher to avoid hypotension, which may result in insufficient blood flow to organs (eg, kidneys in patients with DKD), dizziness, and fainting.

Clinical trial data reviewed by the Seventh Report of the Joint National Committee (JNC 7) support reducing SBP to <140 mmHg and DBP to <90 mmHg. This was confirmed by the panel members of the Eighth Joint National Committee for ages 60 years and younger. For ages 60 years and over, the latter recommended reducing SBP to <150 mmHg and DBP to <90 mmHg. The 2017 ACC/AHA guidelines recommended reducing to <130 mmHg systolic and to <80 mmHg diastolic, based on new data from SPRINT. Systolic blood pressure had not been evaluated as rigorously as diastolic until SPRINT looked at SBP control and clinical outcomes. For patients with elevated blood pressure and elevated ASCVD risk, aggressive treatment of HTN provides significant improvements in clinical outcomes. Recent data suggest that a SBP target of <130 mmHg is reasonable.

In all guidelines, accurate BP measurement using automated office BP measurements or home BP measurement was recommended. A sustained decrease in SBP of 10 mmHg or DBP of 5-6 mmHg for patients with hypertension decreases the risk of stroke by 35-40% and decreases the chance of coronary heart disease by 20-25%.

For patients with diabetes, goals for blood pressure treatment have been evaluated in several randomized trials, particularly ACCORD. SPRINT did not include patients with diabetes. For DBP, a target of ≤90 and likely ≤80 mmHg provides marked benefits. Caution is suggested when DBP falls below 70 mmHg. Mortality increased when patients with diabetes had DBP below 70.

The American Diabetes Association’s 2019 Standards for Medical Care in Diabetes synthesize results from ACCORD and SPRINT by focusing on diabetes as a risk factor for ASCVD. The ADA recommends that BP targets for patients with diabetes be based on the patient’s ASCVD status and 10-year risk for ASCVD, consistent with the ACC/AHA approach to setting BP targets based on ASCVD and ASCVD risk. The one difference is that for a BP target of <130/80 mmHg, ACC/AHA set 10-year ASCVD risk level at ≥10% and the ADA set the level at ≥15%. This difference is of little practical consequence. The effect of increasing age on the calculation of ASCVD risk is sufficiently strong than anyone with an estimated 10-year risk that is >10% and <15% will have an estimated risk ≥15% within a couple of years. Using 10-year ASCVD risk level of ≥10% initiates lowering the goal to <130/80 mmHg slightly earlier.

Blood pressure assessment and treatment. Blood pressure should be measured at all clinic visits for patients with diabetes, and treatment is more aggressive than for patients without diabetes. If diastolic blood pressure is ≥ 90 mmHg or systolic blood pressure is ≥ 140 mmHg on two visits, antihypertensive therapy should be instituted (Tables 6 and 9). Lifestyle modification with dietary alteration, physical activity, and weight loss (if indicated) should be advocated. However, expert opinion from The Seventh Report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC VII) recommends that in patients with diabetes, lifestyle measures should nearly always be augmented by pharmacologic therapy.

Initial treatment is based on severity of hypertension. Patients with blood pressure ≥140/90 mmHg, a single agent can be initiated. Patients with blood pressure ≥160/90 mmHg, initial treatment should include a two drug therapy.

The choice of first-line antihypertensive drugs for patients with diabetes is controversial and not entirely based on the available literature. In the ALLHAT trial, the largest and most representative direct drug-vs.-drug comparison to date, a strategy beginning with a thiazide diuretic (chlorthalidone) reduced myocardial infarction as much as strategies beginning with other agents and reduced stroke and congestive heart failure more than beginning with other agents. That result held across all subgroups, including patients with diabetes. The ADA guidelines recommends Angiotensin-converting enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) as first-line therapy for hypertension in patients with established coronary artery disease and diabetes (HOPE trial).

ACE inhibitors and ARBs reduce progression of established diabetic renal disease and reduce cardiovascular mortality (HOPE trial). Thus, ACE inhibitors or ARBs are recommended as first-line therapy in patient with albuminuria (urine albumin-to-creatinine ratio [UACR] ≥30 mg/g). An important note is that the combination of ACE inhibitors and ARBs should be avoided. Although together they reduce blood pressure and proteinuria, they also clearly increase the rate of end-stage renal disease and mortality. In patients without albuminuria or kidney disease, ACE inhibitors and ARBs have not been found to be superior for cardioprotection when compared to thiazide-like diuretics and dihydropyridine calcium channel blockers.

Dihydropyridine calcium-channel blockers was superior in reducing cardiovascular events when in combination with a renin-angiotensin system blocker (benazepril) compared to hydrochlorothiazide in patients with diabetes (ACCOMPLISH trial).

Beta-blockers are also effective agents in controlling blood pressure, but should probably be added after thiazides and ACE inhibitors, ARB or dihydropyridine calcium channel blockers (see Table 8). Beta blockers are beneficial for treatment of prior MI, active angina, or heart failure but have not been shown to reduce mortality in absence of these disease states. In patients taking insulin for Type 2 diabetes, beta blockers can worsen hypoglycemia episodes particularly during acute illness or hospitalization.⁵⁶ Other classes of agents have not been as rigorously evaluated in patients with diabetes. Alpha-blockers are not recommended, as they appear to deliver less improvement in outcome than other agents.

Low-dose thiazide diuretics (eg, 12.5 to 25 mg of hydrochlorothiazide or 25-50 mg chlorthalidone) do not appear to have clinically important adverse effects, and have been proven to reduce mortality in patients with diabetes. High-dose thiazide diuretics have been reported to have a variety of adverse effects including worsening of hyperlipidemia, hyperuricemia and gout flares, deterioration of glycemic control, impotence, and increased mortality, therefore thiazides should be used at low doses.

Patients with coronary disease or congestive heart failure (CHF) should receive beta-blockers unless a clear contraindication exists. Beta-blockers may decrease high density lipoprotein (HDL) and increase triglyceride levels. In one major trial, beta-blockers led to more weight gain and higher requirements for glucose-lowering agents than ACE inhibitors. If a beta-blocker is used, it should be cardioselective to minimize side-effects.

Patients with CHF or coronary disease with diminished left ventricular function should receive an ACE inhibitor, or an ARB (if ACE inhibitors are not tolerated). ACE inhibitors can lead to cough in up to 20% of patients. Both ACE inhibitors and ARBs can precipitate renal insufficiency and hyperkalemia. Careful monitoring of renal function and serum electrolytes is warranted with these agents.

Regardless of initial agent, most patients with type 2 diabetes will require multiple agents in order to achieve their blood pressure goal. Indeed, many patients will not achieve their goal even with the use of 3 or 4 agents. Further evaluation for secondary causes of hypertension should be considered in these patients.

Lastly, there has been small evidence suggesting reductions in ASCVD events when dosing at least one antihypertensive medication in the evening vs morning.⁵⁷

Lipid screening and treatment

Prescribe at least a moderate potency statin for patients with Type 2 diabetes who are ≥40 years old. Avoid statins in women who are contemplating pregnancy or may become pregnant.

Hyperlipidemia is common in patients with type 2 diabetes. Characteristically, they have elevated triglyceride levels, while HDL levels are low, and LDL levels are typically normal or elevated. Given the high prevalence (up to an 80% lifetime risk) of vascular disease in patients with diabetes, the National Cholesterol Education Program (NCEP) suggests that lipid-lowering treatment is an essential component of diabetes care.

Expert opinion suggests that annual lipid profile provides a check on statin adherence and an opportunity to reinforce lifestyle modifications – the cornerstone of ASCVD risk reduction.

A non-fasting lipid profile is adequate to assess cardiovascular risk and to monitor statin compliance. If lipids are obtained non-fasting and are abnormal (ie, TC >200 mg/dL, HDL-C <40 mg/dL, or triglycerides >500 mg/dL,) consider obtaining a follow up fasting lipid panel to better evaluate for dyslipidemias.

Current ADA and AHA guidelines recommend that for patients with diabetes and known ASCVD or ASCVD risk greater than 20%, treatment should be initiated with high dose statin. If LDL <70 mg/dL or non-HDL cholesterol ≥100 mg/dl is not achieved on maximally tolerated statin therapy, addition of a second agent, like ezetimibe or a PCSK9, should be considered. For patients with diabetes who are <40yo, a statin should be started if LDL ≥190 mg/dL with goal of achieving a 50% reduction.

For patients with diabetes under the age of 40, and without extreme elevations of LDL, a moderate dose statin could be considered if there are multiple ASCVD risk factors.

For patients with diabetes 40-75 years old without known ASCVD and an ASCVD risk <20%, at least a moderate potency statin should be started. For patients with diabetes >75 years without known ASCVD and an ASCVD risk <20%, any previously prescribed statin should be continued. Consider a moderate dose statin for patients with diabetes age >75 years without known ASCVD after a risk/benefit discussion.

The issue of LDL targets is controversial. Experts have suggested LDL targets of less than 100 or even 70 mg/dL for patients with diabetes. However, few studies have established a specific LDL target level; instead nearly all trials compared the efficacy of a fixed dose of a statin with placebo. The best evidence suggests that patients receive about the same level of benefit across all baseline LDL levels and with any degree of LDL reduction. This suggests that the benefits of statins are not fully captured by LDL and argues for their empiric use. A reasonable approach is to start most patients with diabetes on moderate potency statins, (eg, lovastatin [generic] 40 mg/dL) without specific LDL targets. For secondary prevention, essentially all patients with diabetes should be on statins; some evidence supports the use of higher dose statins in these populations (eg, rosuvastatin 40 mg/dL or atorvastatin 40-80 mg/dL), particularly in those who are admitted for acute coronary syndrome. Avoid prescribing simvastatin 80 mg because of the increased risk of myalgias. Careful monitoring of potential drug interactions with statins is critical; many drugs can increase the risk of myalgias and rhabdomyolysis when combined with statins.

Non-HDL is a measurement of all atherogenic lipoproteins (lipoprotein(a), very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low-density lipoproteins (LDL)). Unlike LDL, non-HDL is not dependent on fasting and is more accurate when triglycerides are elevated. Non-HDL thresholds for adults should be 30 mg/dL higher than the equivalent LDL threshold.

Statins may not be appropriate in some patients with diabetes, especially those with severe, chronic malnutrition from pancreatic insufficiency, or women planning pregnancy. When deciding to start a statin, consider the patient’s 10 year ASCVD risk, nutritional status and life expectancy.

In patients with diabetes, observational data suggest that triglycerides are also an independent risk factor for the development of atherosclerotic disease. However, only very limited trial data evaluate the effectiveness of lowering triglycerides on cardiovascular outcomes. The first-line of treatment for hypertriglyceridemia is optimization of glucose and thyroid (if hypothyroid) control. Use of fibrates is generally discouraged as there is no evidence of benefit in trials using fibrates alone or in combination with statins. If triglycerides are markedly elevated (eg, >500 mg/dL), then treatment may be warranted to avoid pancreatitis.

Non-alcoholic fatty liver disease (NAFLD)

It is estimated that approximately 25-30% of adults in the United States have underlying NAFLD.⁵⁸ NAFLD has been reported in one- to two-thirds of adult patients with type 2 diabetes.^59,60 Despite this high prevalence, there is some debate about routine screening in high-risk patient groups “because of uncertainties surrounding diagnostic tests and treatment options, along with lack of knowledge related to long-term benefits and cost-effectiveness of screening”.⁶¹ It is recommended that clinicians maintain a high index of suspicion for NAFLD and Non Alcoholic Steatohepatitis (NASH) in patients with type 2 diabetes.⁶¹ In the 2021 ADA guidelines, patients with type 2 diabetes who have elevated transaminases or evidence of fatty liver on ultrasound should be evaluated for NASH and fibrosis.⁶² Non-invasive risk-stratification tools may be helpful to identify individuals at low or high risk of advanced fibrosis. These include serologic biomarker calculators like the NAFLD fibrosis score (NFS), the fibrosis-4 index (FIB-4) or vibration controlled transient elastography (VCTE).⁶¹ Non-alcoholic steatohepatitis (NASH) is a subgroup of people with NAFLD who have inflammation in addition to fatty infiltration and are thus at high risk of progression to cirrhosis. NASH is currently one of the leading indications for liver transplant in the US. The only way to definitively diagnose NASH is by liver biopsy. The primary treatment that slows the progression of NAFLD/NASH is diet, exercise, and weight loss with strong evidence for benefit from adopting a Mediterranean diet or a low carbohydrate diet.^7,8 Additional benefits may come from decreasing or eliminating alcohol consumption, vaccinating against hepatitis A and B, screening for hepatitis C, and treating if appropriate, avoiding liver toxic medications, supplements, and alcohol. Preliminary data supports the use of SGLT-2 inhibitors and GLP-1 agonists and larger trials of these medications are ongoing.^10,63 Individuals identified as being high risk for advanced fibrosis, or individuals with indeterminate risk assessment scores and multiple metabolic comorbidities, may benefit from referral to GI/Hepatology.

Obesity

Obesity is increasing worldwide and contributes to the rise of not only type 2 diabetes, but also hypertension, hyperlipidemia, macrovascular disease, osteoarthritis, and other conditions. The treatment of obesity is central to the comprehensive treatment of type 2 diabetes in many cases. Lifestyle interventions for obesity, medications to promote weight loss, and bariatric surgery should all be considered in the approach to the obese patient with type 2 diabetes.

The majority of patients with type 2 diabetes have overweight or obesity. Weight loss of 5-10% can help patients with type 2 diabetes reduce or eliminate the need for anti-hyperglycemic medications.^13,64 A comprehensive weight management approach that considers individual patients’ barriers to weight loss as well as their needs, preferences, and goals is recommended.

Addressing barriers:

1. Replace obesogenic medications with weight-neutral alternatives, if appropriate.
2. Screen for medical conditions (eg, obstructive sleep apnea, insomnia, Cushing syndrome, hypogonadism, hypothyroidism, polycystic ovarian syndrome, depression, or eating disorders) or life events (eg, marriage, divorce, retirement) that may promote weight gain and/or hinder weight loss.
3. Ask about access to food and refer to Social Work for food insecurity resources, if appropriate

Developing a personalized weight loss plan:

Primary care-based resources: Although Medicine reimburses PCPs for intensive lifestyle counseling (ILC), most PCPs do not have the time or knowledge to engage patients in ILC.⁶⁵ Accordingly, PCPs should consider referring patients with obesity to dietitians, clinical pharmacists and/or evidence-based lifestyle change programs.

Lifestyle change programs: Lifestyle programs aim to help patients lose weight through diet and physical activity changes. Patients should be educated that dietary changes are key to weight loss (see Nutrition section). Exercise promotes cardiovascular and mental health benefits, but is not required for weight loss. Exercise does, however, play a key role in weight loss maintenance.⁶⁶ Commercial lifestyle change and meal replacement programs supported by the literature include: Weight Watchers, Jenny Craig, Nutrisystem, Medifast, Optifast, Atkins, Slim-fast, TOPS and Health Management Resources.^66–68 Vitra Health’s online keto diet program for people with type 2 diabetes has been shown to induce diabetes remission in some type 2 diabetes patients.⁶⁹

Pharmacotherapy: May be considered in patients who have failed to reach weight loss goals through lifestyle modification alone, have obesity-related health issues, and have BMI >30 kg/m2; or BMI >27 and at least one obesity-related health condition. A list of potentially obesogenic medications and non-obesogenic alternatives is listed in Table 11. Table 12 lists medications for weight loss.

Table 11

Obesogenic medications and alternatives for common conditions ,.

Table 12

Medications for Weight Loss ,,.

Supervised medical weight loss: Often includes very low energy meal replacement (<800 kcal per day).

Weight loss surgery: Gastric bypass, laproscopic gastric banding, sleeve gastrectomy, or biliopancreatic diversion with duodenal switch may be considered in patients with BMI ≥40; or BMI ≥35 and suffer from an obesity-related condition.^70,71 Consider a patient who is prepared and willing to commit to lifestyle changes that will be necessary after surgery eg, non-smoker; failed to lose weight with other approaches. These are associated with improvement or resolution of obesity-related chronic conditions and reduced mortality.^72,73

Regardless of the treatment use, weight regain can occur. Strategies to promote weight loss maintenance (ie, maintain body fat mass within +5%) include regular physical activity, continued dietary adherence, self-weighing, and maintaining food log.⁷⁴

Psychological comorbidities

• Psychosocial care should be integrated into a collaborative patient-centered approach and provided to all people with diabetes.
• Consider assessing depression, diabetes distress, anxiety, eating disorders, and cognitive capacities using validated tools at the initial visit, at periodic intervals, and when there is a significant change in health, treatment, or major life circumstances. Caregivers and family members should be included when this is appropriate.

Pain

In addition to causing diabetic peripheral neuropathy, diabetes predisposes to chronic musculoskeletal pain. Observational studies have shown an increased risk for chronic back, shoulder, and neck pain. Diabetes appears to increase disability and emergency room visits due to chronic pain. Chronic pain may be a barrier to achieving diabetes-related benchmarks. Chronic pain presents a major barrier to frequent exercise, which is a key part of diabetes management. Low impact activities such as yoga, tai chi, and warm pool-based exercise have all been shown to improve quality of life and some diabetes-related outcomes.

Macrovascular Disease

Diabetes increases an individual’s risk of coronary artery disease, stroke, and peripheral vascular disease. Reducing other cardiovascular risk factors (Table 9) in patients with diabetes reduces their overall risk. Cardiovascular risk factors should be assessed annually in patients with type 2 diabetes. These risk factors include hyperlipidemia, hypertension, smoking, a family history of premature coronary disease, obesity, and the presence of micro- or macroalbuminuria.

Aspirin

The ADA and most other organizations recommend use of aspirin for secondary prevention in all patients with diabetes who have known atherosclerotic cardiovascular disease. However, the use of aspirin for primary prevention of atherosclerotic disease events is not recommended form most people with diabetes as a routine practice. Recent data do not consistently show that aspirin used for primary prevention leads to a decrease in major cardiovascular events. Aspirin used for primary prevention increases the occurrence of major bleeding events such as GI bleeding and intracranial hemorrhage due to falls.^75–78 This is an area of ongoing debate and research. The USPSTF states that there is some evidence to support using aspirin for primary prevention for patients between the ages of 50 and 69 who are at high risk for adverse CVD events and at low risk for GI bleeding.⁷⁹

SGLT2 inhibitors and GLP-1 RAs

Multiple randomized controlled trials have demonstrated the cardiovascular benefit of these drug classes in people with type 2 diabetes.^80–85 A reduction in major adverse cardiovascular events (MACE) and in some instances a reduction in mortality have been demonstrated for members of both these drug classes. These findings have led the ADA to recommend initiation of these drugs for diabetic patients with history of ASCVD or those at high risk for ASCVD. The term “high risk” has been variably defined, but generally includes individuals without history of ASCVD but presence of classical CVD risk factors such as hypertension, LDL >140, LVH, and tobacco smoking. Review the Glycemic Management section for a more information on the efficacy of the SGLT-2 inhibitors and GLP1-RAs.

Screening for Coronary Artery Disease

Clinicians should maintain a high index of suspicion for macrovascular disease in patients with type 2 diabetes. Symptoms suggestive of coronary artery disease, transient ischemic attack, stroke, or peripheral vascular disease should prompt consideration of further testing.

Screening for coronary artery disease in asymptomatic individuals is not recommended as a routine practice. A large randomized control trial demonstrated that screening for CAD in asymptomatic type 2 diabetes did not reduce the rate of cardiac death or myocardial infarction.⁸⁶

However, screening for coronary artery disease may be considered for individuals over age 30 with type 2 diabetes and additional risk factors for CVD who wish to start an exercise program more rigorous than a brisk walk. The prospective Look AHEAD study showed 22% of people with diabetes who were asymptomatic of coronary artery disease displayed objective abnormalities on exercise ECG stress testing.⁸⁷

Cardiovascular Autonomic Neuropathy

Cardiovascular autonomic neuropathy (CAN) is defined as the impairment of autonomic control of the cardiovascular system. CAN is particularly concerning because it may lead to silent ischemia and/or silent myocardial infarction. CAN may manifest clinically as resting tachycardia, orthostatic hypotension, syncope, impaired blood pressure/heart rate response to exercise, and exaggerated drop in blood pressure/heart rate during induction of general anesthesia.

Autonomic neuropathy and cardiovascular disease

Although less common in Type 2 than Type 1 diabetes, autonomic neuropathy can occur. This is primarily of concern in the detection of cardiovascular disease, as angina may be silent in adults with diabetes. Care should be taken to elicit a history of possible atypical anginal symptoms or equivalents and consideration should be given to risk assessment and stress testing.⁸⁸

Microvascular Complications

Include microvascular disease in screening and treatment (Table 7).

Retinopathy

Retinopathy and macular edema affect a substantial proportion of patients with Type 2 diabetes. Between 10 and 30% of subjects have retinopathy at the time of diabetes diagnosis, and most will eventually develop some level of retinopathy. Severe retinopathy requiring treatment is somewhat less common, but still makes diabetes the leading causes of visual loss in US adults and the leading cause of blindness in working age adults. Prevention of retinopathy is best achieved by optimizing blood pressure and glucose control.

Dilated retinal examination reduces the incidence of severe visual loss by allowing timely treatment (eg, laser photocoagulation, anti-VEGF intraocular injections) of proliferative retinopathy and macular edema. Optimal screening intervals for retinopathy depend on the risk in the individual patient. Patients who have been diagnosed with retinopathy should be screened at least annually, and many will require much more frequent examination depending on the degree of retinal abnormality. Patients have a low risk of developing retinopathy that will require treatment over the short term if they have no retinopathy on a baseline retinal exam by an expert and have both reasonable glucose and blood pressure control. These patients can be screened less frequently, at 2 year intervals. For measuring quality of care for diabetes, the HEDIS interval for retinal examinations is biennially for patients with previous normal eye exam and at least annually for patients with abnormal eye exam.

Unless the primary caregiver has been specifically trained to perform dilated retinal examinations, the accuracy of fundoscopic examination is poor. Thus, all screening should be performed by a trained eye-care professional.

Glucose-lowering drugs capable of producing rapid drops in A1c have been associated with increased rates of diabetic retinopathy. Insulin, sulfonylureas, TZDs, and GLP1-RAs have all been associated with increased rate of retinopathy presumable due to rapid reduction in glucose levels. If these medicines are being initiated, more frequent A1c checks and fundoscopic exams should be considered.

Nephropathy

Diabetic nephropathy affects 20%-40% of patients with diabetes and is the single leading cause of end-stage renal disease (ESRD) in the United States. A CDC analysis showed the age-adjusted incidence of ESRD caused by diabetes declined by one-third from 1996 to 2007, which may be related to more screening and aggressive use of ACE/ARB in treatment of blood pressure. Yearly screening and treatment for microalbuminuria can reduce the incidence of renal failure. The spot urinary albumin-creatinine ratio is a simple method for testing for microalbuminuria. Because of day-to-day variation in urinary albumin excretion, the test should be repeated on at least two more occasions over a 3- to 6-month period, if the first test result is positive. Two of three tests should be positive (>30 mg albumin per gm of creatinine) before microalbuminuria is considered present. Albuminuria is defined as albumin excretion >300mg/day.

Causes of elevated urinary albumin excretion in the absence of diabetic nephropathy include urinary tract infection, recent exercise, acute febrile illness, hematuria related to urinary tract infection (UTI) or menses, and congestive heart failure. If screening microalbumin is >30 mg/dL, check urinalysis to assess for other causes.

Microalbuminuria is a marker for greatly increased cardiovascular morbidity and mortality for patients with diabetes. Therefore, aggressive intervention is recommended to reduce all cardiovascular risk factors (eg, lowering of LDL cholesterol, antihypertensive therapy, cessation of smoking, institution of regular physical activity, etc.).

For people with diabetes and diabetic kidney disease (either micro- or macroalbuminuria), reducing the amount of dietary protein below usual intake is not recommended because it does not alter glycemic measures, cardiovascular risk measures or the course of GFR decline. Consider dietary referral to evaluate dietary protein in patients with proteinuria.

Multiple glucose lowering drugs have been shown to improve renal outcomes. A 2019 meta-analysis of RCTs that included patients with DKD and GFR>30 mL/min/1.73m² showed SGLT2 inhibitors reduced the incidence of decline in GFR, need for renal replacement therapy, doubling of serum creatinine, and development of albuminuria.⁸⁹ DPP4 inhibitors have been shown to decrease albuminuria. GLP1-RAs have been shown to reduce development of albuminuria. The evidence favors SGLT2 inhibitors, compared to other drug classes and therefore, should be considered for glycemic management in patients with DKD with a GFR of >30 mL/min, whose A1c is above goal. However, SGLT2 inhibitors have been associated with genitourinary tract infection, acute renal failure, and increased risk of diabetic foot amputation, therefore consider the risk factors carefully.

ACE inhibitors reduce the rate of progression from microalbuminuria to overt proteinuria and diabetic nephropathy, independent of their effect on blood pressure. ARBs show similar benefits to ACE inhibitors in patients with type 2 diabetes and microalbuminuria and diabetic nephropathy. Direct comparisons between ACE inhibitors and ARBs have not been performed in patients with type 2 diabetes. ACE inhibitors and ARBs are regarded as functionally equivalent in protecting against progressive diabetic nephropathy, although more evidence exists in the literature for therapy with an ARB to continue to show benefit even up to the development of end stage renal disease. An ACE inhibitor or an ARB should be used in all patients with microalbuminuria. Combination ACE/ARB therapy for patients with persistent albuminuria is NOT recommended. While the combination reduces proteinuria, it also increases renal failure and adverse events in patients with diabetes, without any benefits on cardiovascular or renal outcomes.

Other antihypertensives (including beta-blockers and non-dihydropyridine classes of calcium-channel blockers (NDCCB) can reduce the level of albuminuria, but no antihyptertensive studies to date have demonstrated a reduction in the rate of fall of GFR. Some members of the dihydropyridine class of calcium channel blockers (eg, nifedipine, felodipine) may increase urinary albumin excretion, and should be avoided in patients with microalbuminuria.

Control of blood pressure is important. Recommended blood pressure goals in patients with diabetes and chronic kidney disease are:

In normotensive patients with microalbuminuria, target dosages of ACE inhibitors are difficult to define. Some experts recommend titrating medications upward until a normal albuminuria is seen or side effects occur.

For further information regarding care of patients with chronic kidney disease, see the UMHS clinical guideline on Chronic Kidney Disease.

Neuropathy

Diabetic neuropathy is reported in up to half of patients with diabetes. Most have loss of sensation, only a minority experience pain. Patients often describe pain as burning, shock sensation, or stabbing. Evidence indicates early detection of diabetic neuropathy and aggressive foot care results in fewer foot ulcers and amputations. Pay careful attention to the etiology of pain. Occasionally, mechanical factors rather than neuropathy are the mechanism underlying pain.

Glucose lowering medications may have an effect on neuropathy-related complications. GLP-1-RAs have been shown to decrease the risk of diabetic foot ulcer complications. Though SGLT-2 inhibitors on the whole have not been shown to increase the risk of diabetic foot ulcer complications, the CANVAS study results suggest that canagliflozin increases the risk of lower extremity amputations.⁴⁸ Risk factors for lower limb amputation should always be considered prior to initiation of this drug class. Risk factors for lower limb amputations include significant peripheral neuropathy, peripheral arterial disease, diabetic foot ulcer, and prior amputation.

Diabetic foot care. Foot care includes examination, preventive care, consideration of orthotic footwear, and treatment of foot ulcers.

Examination. Perform a visual foot inspection, pulse and sensation check annually, and with every routine visit if abnormalities are present. Identify areas of callus formation, claw toe deformity, prominent metatarsal heads (or other bony prominences), and other structural changes. Three simple tests detect peripheral neuropathy: pressure sensation, vibration sensation and temperature/pain perception.

Perform sensory testing with a 5.07 (10g) nylon monofilament annually, to identify insensate feet without protective sensation. Instructions on “How to Use a Monofilament” are in Table 10. Individuals with insensitive feet are at high risk of developing foot ulcers and other related complications.

Table 10

How to Use a Monofilament to Test for Foot Neuropathy.

Education. All patients require education regarding optimal foot and nail care, which includes daily inspection and appropriately fitting shoes. To minimize the risk of trauma, patients should be counseled to avoid walking barefoot and those with neuropathy should avoid high-impact exercise and the use of hot water.

Footwear. Orthotic footwear should be prescribed to accommodate major foot deformities and off-load pressure areas. Most insurance plans, including Medicare, cover therapeutic footwear for patients with diabetic neuropathy or deformity. For others with less deformity, athletic shoes with sufficient room for the toes and forefoot and cushioned socks are appropriate.

Foot ulcers. Detection and early treatment of foot ulcers is of paramount importance. Foot ulcers are among the most common reason for hospitalization in people with diabetes and are the leading cause of lower extremity amputations. However, evidence suggests that up to 85% of amputations are avoidable with patient education, medical monitoring, and early intervention.⁹⁰ Careful evaluation of vascular status and infection are required upon discovery of an ulcer. Initiate early treatment with aggressive wound care, antibiotics, revascularization, orthotic prescriptions, and casting to offload the ulcer when appropriate. Studies have shown patients with diabetic foot ulcers have the best outcomes if managed by a multidisciplinary team that specializes in diabetic foot care. Hyperbaric oxygen therapy may be recommended in managing diabetic foot ulcers, although trials have shown mixed results.

Treatment of painful diabetic peripheral neuropathy (PDN)

Optimizing glycemic control is of paramount importance in slowing the progression of established diabetic neuropathy. Consider checking and treating vitamin B12 level in patients who use chronic metformin as vitamin B12 deficiency can contribute to worsening of neuropathy.

NSAIDS should not be used for chronic neuropathic pain as they are ineffective and increase cardiovascular risk, GI, and renal side effects. Long term NSAID treatment increases the risk of GI bleeding and renal insufficiency. NSAID use in patients with heart disease or its risk factors increases overall risk of heart attack or stroke.⁹¹

First line therapies for the treatment of PDN supported by the literature include pregabalin, duloxetine, and gabapentin. Pregabalin and duloxetine have FDA approval for treatment of neuropathic pain in diabetes. Tricyclic antidepressants (TCAs) are also options. Comparative effectiveness studies and trials that include quality of life outcomes are rare – so treatment decisions must consider patient’s comorbidities, presentation, symptom improvement, medication adherence, and side effects.

• Pregabalin (up to 300-450 mg/day as divided doses) is FDA-approved and is less sedating. Most extensively studied and have favorable effects with at least 30-50% improvement in pain. Starting at 25-75 mg once daily or in divided doses then titrating up to lowest effective tolerable dose will minimize side effects especially in elderly patients.
• Duloxetine (60-120 mg/day) and venlafaxine (75-450 mg/day), serotonin and norepinephrine reuptake inhibitors (SNRIs) are useful in treating patients with co-morbid depression. Duloxetine is FDA-approved. It has been shown to improve neuropathy-related quality of life. Selective Serotonin Reuptake Inhibitors (SSRIs) and trazodone are not as effective in treating painful PDN.
• Gabapentin up to 900-3600 mg/day as divided doses, or more may be required. Use lowest effective dose. Sedation is a side effect that limits its use. May be a less expensive option.
• TCAs may be used to treat painful neuropathy. Use with caution in the elderly and start with low doses and titrate to maximize pain relief while minimizing side effects. Most common side effects include: dry mouth, sedation, orthostatic hypotension and constipation. Nortriptyline is the preferred tricyclic as it has fewer anticholinergic properties. Recommend initiating with dinner, a dose of 10-25 mg and titrate up as tolerated, to maximum of 150 mg/day.

Other agents. Carbamazepine (200 – 600 mg/day) and valproate (500 mg/day), topical capsaicin cream, and lidocaine patch have been shown to decrease PDN. Their use is limited by their side effect profiles.

Opioids. Tapentadol Extended Release is FDA approved for the treatment of neuropathic pain associated with diabetes based on data from two multicenter clinical trials but the design included patients who responded to tapentadol and therefore is not generalizable. As a last resort, opioids may be considered, though general use is discouraged given high risk for addiction and safety concerns compared to the relatively modest pain reduction. Tramadol is a weak opioid and dose of 37.5 mg with 325 mg acetaminophen showed an improvement in PDN compared to placebo. Refer to the UMHS Clinical Care Guideline “Managing Chronic Non-Terminal Pain in Adults Including Prescribing Controlled Substances“.

Acupuncture and TENS. Several studies have shown the efficacy of using traditional acupuncture for the treatment of painful diabetic neuropathy. Transcutaneous Electrical Nerve Stimulation (TENS) has also been evaluated and has been shown to reduce lower extremity pain associated with PDN. Hyperbaric oxygen therapy as an adjunct therapy to standard treatment has been shown to reduce cell death, pain symptoms and rates of major amputations in patients with diabetic foot ulcers and peripheral arterial occlusive disease.

Immunizations

Patients with diabetes should get the usual vaccinations recommended for the general population. Particular attention should be paid to influenza vaccination (annually) and Hepatitis B due to the increased risks for these diseases in patients with diabetes. In addition, patients with diabetes, regardless of their age, should be given Pneumovax 23 for pneumococcal pneumonia. If vaccination occurred prior to the patient turning age 65, a second dose is required at least 5 years after receiving the first dose. Patients over age 65, who were not previously vaccinated should receive one dose of Pneumovax 23.