DIABETES MELLITUS IN ADULTS
• Screening for diabetes should be done in high-risk populations, especially:
• Those with prediabetes or the metabolic syndrome.
• High-risk ethnic groups (e.g., Native American, Latino American, African American).
• History of gestational diabetes.
• Patients might present with atypical symptoms.
• Most diabetes is type 2 in adults, but type 1 does occur in adults, and delayed diagnosis is common.
• Cardiovascular risk should be aggressively screened for and treated.
• Complications should be documented and tracked.
• Check fasting lipids or, if inconvenient, get non-fasting lipids focused on CV risk using a calculator.
• Check renal function and albuminuria yearly.
• Have a low threshold for stress testing, with imaging for all patients who have symptoms.
• Refer for yearly eye examinations by an eye professional.
• Check feet for sensation, deformity, and circulation at regular visits.
• All patients should receive an educational assessment and training in self-management and self-monitoring of blood glucose.
• Take a diet history; this is especially important for patients on insulin.
• Get a baseline HbA1c and repeat 2 to 4 times per year (twice yearly if at glycemic goal).
• Diabetes requires nutrition and behavioral self-management counseling as well as drug therapy.
• Individualize goals for every patient (for glycemia, lipids, BP)
• Base individualization on age, motivation, complications, diabetes duration, hypoglycemia risk
• Repeatedly encourage healthy eating and an active lifestyle.
• Prediabetes diagnosis represents an opportunity for behavioral and drug interventions.
• Metformin (Glucophage) is usually the first drug therapy.
• Don’t expect one drug to do the job for very poorly controlled glycemia, especially if HgbA1c >9%.
• Dual defects (insulin resistance and secretion) should be addressed in most patients.
• Very insulin-resistant patients might need a dual insulin-resistance strategy.
• Therapy goals for both HbA1c and self-monitored blood glucose can be achieved in most patients.
• Cardiovascular risk reduction therapy is a very high priority— statins and BP control best.
• Consider use of new Omnibus calculator for when to start statin therapy.
• When patients have not met goals on two or three oral agents as therapy, basal insulin is often the most appropriate choice, particularly when patients are not near glycemic goals.
• For oral agent therapy, add—don’t switch—unless side effects require it.
• When adding basal insulin, initially continue oral agent therapies.
• Threatening patients with insulin therapy is counterproductive.
• Follow the 3F rule: Fix the fasting glucose first, especially in patients with poor glycemic control. As control improves, pay attention to postmeal sugars.
• Prompt recognition of the need for meal insulin is critical to achieve glycemic goals.
• Usually start with a single-meal insulin dose for the largest meal.
• Balance meal and basal insulin; check post-meal BG.
The Centers for Disease Control and Prevention (CDC) estimated that in 2012 the prevalence of diabetes in the United States was 29.1 million. Diabetes is diagnosed in 21 million persons and undiagnosed in 8.0 million. Type 2 diabetes mellitus (T2DM) is 90% to 95% of prevalent diabetes, and type 1 diabetes (T1DM) is about 5% to 10%.
There are fewer persons with secondary or monogenic forms of diabetes, such as maturity-onset diabetes of the young (MODY). About 86 million people above the age of 20 in the United States are thought to have prediabetes.
The focus of this article is T2DM because it is the most prevalent form and is increasing rapidly in the United States and worldwide. A few comments are made on adult T1DM. This chapter emphasizes both lifestyle and pharmacologic treatments. Although prediabetes may not require drug therapy, it represents an important opportunity to prevent diabetes and initiate critical lifestyle changes.
Diagnosis and Classification of Diabetes and Prediabetes
Most diabetes is diagnosed by random or fasting glucose (Table 1). Symptoms should be present (e.g., thirst, frequent urination) if random glucose criteria are used, but surprisingly, many people with diabetes are relatively asymptomatic. In the elderly, cognitive changes can occur and atypical symptoms such as prostatism or genital yeast infections can suggest the diagnosis. The American Diabetes Association (ADA) screening recommendations suggest screening every 3 years starting at age 45 for the general population, but they suggest earlier and more frequent screening in those with high risk.
Elevated HbAlc when 6.5% or higher can be used for screening and diagnosis of diabetes.
Diagnosis and Classification of Diabetes and Prediabetes
Abbreviations: IFG = impaired fasting glucose; IGT = impaired glucose tolerance.
* Polyuria, polydipsla, unexplained weight loss.
† NGS nationally standardized lab method.
Patients from diabetes-prone ethnic groups (e.g., Latin Americans, African Americans, Native Americans, Asian Americans of several types) or with a strong family history, polycystic ovary syndrome
(PCOS), or gestational diabetes should have early and frequent screenings. High-risk persons include those with prediabetes (impaired glucose tolerance, impaired fasting glucose) or who meet the National Cholesterol Education Program (NCEP) criteria for the metabolic syndrome or its individual components (dyslipidemia, hypertension, central obesity, prediabetes). The metabolic syndrome is flawed, but this does not reduce the importance of fully documenting and treating cardiometabolic risk components in those with or at risk for T2DM in a targeted manner (see Box 1). Teach patients and clinicians about these risks and can encourage the overweight and sedentary to adopt a healthier lifestyle.
|Summary of Goals for Treatment|
Medical Nutrition Therapy (individualized)
• Appropriate calories for weight, 5%–10% weight loss for obese patients
• Low saturated and trans fats, substitute with healthy fats
• Moderate, consistent carbohydrates (whole grains, vegetables, fruits with low glycemic effects)
• Foods that can reduce postmeal sugars (low glycemic load)
• Healthy fats and proteins (decreased saturated and trans fats, increased monosaturated fat; reduced consumption of animal protein)
• Consistent, regular activity tailored to complications and safety (ECG or stress test may be needed before starting an exercise program)
Glycemia: it is critical that these goals are individualized*
• Best possible without frequent or severe hypoglycemia
• HbA1c < 7% generally; 6% or less if possible in selected patients early in disease course; 7%–8% may be appropriate in those with shortened lifespan
Self-Monitored Blood Glucose
• Preprandial 80–130† mg/dL; < 110 ideally; 20–30 mg/dL higher is acceptable for high-risk patients
• Postprandial (1–2 h) < 180 minimal; < 140 ideal
• All DM patients with overt ASCVD should be on high intensity statins
• DM patients < 40 or > 75 years old with CVD risk** consider medium intensity to high intensity statins
• DM patients 40-70 years old with CVD risk consider high intensity statins
• DM patients < 40 without CVD risk statins are not recommended
• Blood Pressure‡
• Systolic < 140 mm Hg
• Diastolic < 90 mm Hg
Abbreviations: ACS = acute coronary syndrome, ASCVD = atherosclerotic cardiovascular disease.
* See ADA guidelines for factors
† 80 mg/dL is too low for patients with high risk of hypoglycemia.
** CVD risk factors include LDL cholesterol ≤100 mg/dL (2.6 mmol/L), high blood pressure, smoking, and overweight and obesity.
‡ More aggressive BP goals may be appropriate for individual patients if there are no increase in risk of side effects. Relaxed criteria based on age, comorbidities, long duration of diabetes, behavioral, motivational criteria and others.
The classification of diabetes into its two most prominent types (T1DM and T2DM) seems straightforward in theory but in practice is increasingly confusing as more Americans become overweight.
Although T1DM patients are traditionally lean, many now are overweight and some have metabolic syndrome characteristics. About 80% to 90% of persons with T2DM are overweight or have metabolic syndrome characteristics, but some are leaner and more active and do not have the metabolic syndrome. C-peptide measurements are not very helpful for those who are difficult to classify, but measuring three antibodies—including IA-2 (islet cell antigen 512), anti-GAD65 (glutamic acid decarboxylase), and anti-insulin antibodies in high titers—can clarify a diagnosis of latent autoimmune diabetes. Younger age at onset, lean body habitus, severe loss of glycemic control with or without ketonemia, and weight loss all suggest insulin deficiency but might not be definitive.
Optimal glycemia goals must be individualized, but may be generally defined as hemoglobin A1c (HgbA1c) of less than 7% (see Table 1) as recommended by the ADA. Pre-prandial capillary blood glucose should be 80–130 mg/dL and postprandially at the peak (typically about 2 hours after meals) they should be generally less than 180 mg/dl. Individualizing glycemic goals should be based on several factors including: duration of diabetes, the age and life expectancy, comorbid conditions such as known cardiovascular disease, advanced microvascular complications, hypoglycemia unawareness and other individual patient considerations. Both HgbA1c and capillary blood glucose concentrations should be individualized to reduced hypoglycemic risk. A summary of other goals is given in Box 1.
The primary causes of most adult diabetes are insulin resistance and lack of compensatory insulin secretion. Abnormalities in incretin hormone physiology may also underlie early pathophysiology although deficiency of GLP-1 is probably not the simple explanation. Insulin resistance is typically longstanding and begins at a young age because of heredity combined with environmental causes (sedentary lifestyle and calorie overconsumption with resultant overweight).
Insulin secretory defects usually start about 10 years before diagnosis, and no therapy is proven so far to prevent progressive loss of insulin secretion. A few patients develop diabetes associated with malnutrition, but this is much less common. Longstanding insulin resistance is associated with dyslipidemia, central obesity, hypertension, and hyperglycemia. This long prodrome accounts for the common coexistence of cardiovascular disease and diabetes.
Cardiovascular Risk Management
Cardiovascular risk management in diabetes starts with lifestyle counseling and education. It is paramount that patients understand the intimate and direct links among diabetes, glycemic control, and cardiovascular disease. Drug interventions are ultimately needed for glycemia, lipid risks, and blood pressure in most patients. Women have higher relative risk and similar overall risk as men and are often undertreated. Specific recommended targets of therapy for diabetes in glycemia, blood pressure, dyslipidemia, and lifestyle are shown in Box 1.
Documenting and Following Complications
Patients should have a thorough examination and evaluation for complications at the time of diabetes diagnosis. About half of patients with newly diagnosed T2DM have established chronic complications, indicating delayed recognition of this disorder.
Neuropathy and circulatory signs and symptoms on foot examination should be assessed. Risk of ulcer and amputation can be gauged by 10-g Semmes-Weinstein monofilaments that test for severe neuropathy and attendant risk of ulceration. Retina examinations should be done by skilled eye professionals likely to pick up significant eye disease. High-risk patients (poor glycemic control, established retinopathy, especially if preproliferative or worse) should be referred promptly to an eye specialist. Pregnancy counseling should be given to all women of childbearing age with diabetes.
Albumin-to-creatinine ratio in the urine should be assessed and kidney function (serum creatinine, estimated glomerular filtration rate [eGFR], and blood urea nitrogen [BUN]) should be tracked yearly.
Many drugs for diabetes are dosed based on kidney function so it may be appropriate to track eGFR closely (e.g., every 3–6 months) when it is abnormal.
Home glucose monitoring should be taught to patients so they understand the effects of food, stress, and exercise on glycemic patterns. Diabetes education should be arranged for all patients, preferably by a diabetes educator. Diabetes is unique in being a self- managed condition where patient knowledge and skills are critical to avoiding complications. Moreover, behavioral management is critical to success in diabetes care.
Self-management of behavioral factors, including eating, physical activity, and psychological stress, is essential to good diabetes self- care. Ideally, professional support for behavioral self-management should be a coordinated, multidisciplinary effort involving expertise appropriate to a given patient from the areas of nutrition, nursing, physical activity, and behavioral counseling. The provider should develop basic behavior change skills and refer to appropriate multidisciplinary and community-based resources.
Quick, one-shot interventions seldom change longstanding patterns of behavior. Initial sessions should be scheduled close together (1–2 weeks), then further apart as the patient gains momentum and confidence. If multiple one-on-one sessions are impossible, other options such as group meetings, telephone support, or e-mail messaging should be considered.
Behavior change interventions should be highly individualized and specific. General advice about diet and exercise does not address the life experience or problems of a given patient and is often perceived as insensitive or unhelpful. Arriving at individualized objectives for behavior change can be accomplished using a simple three-step process composed of initial assessment, setting behavioral objectives, and follow-up and reassessment.
Initial assessment includes identifying salient features of social and family history that can affect efforts to change behavior. A nutrition assessment should be performed, including an appraisal of usual food intake, the patient’s perception of problem eating behavior, and weight history. A physical activity assessment should also be conducted, focusing on past and current physical activity, preferences, perceived barriers, and general attitudes. Readiness to make changes in behavior should be assessed by asking how important a patient thinks it is to change a given area of behavior and how confident she or he is that she or he can succeed in making changes (on a 1 to 10 scale). Discussion of specific objectives for behavioral change should occur in areas where the patient indicates a definite readiness to begin. Finally, ask patients about current levels and sources of stress. Because depression is common with diabetes, patients should be screened for possible depression.
Setting behavioral objectives is initiated and facilitated by the provider, but the patient is responsible for selecting his or her own behavioral objectives. Objectives should be FIRM: few (1–3 at a time is plenty), individualized to the patient’s specific behavioral challenges, realistic (beware of trying to make big strides quickly), and measurable. The patient should be encouraged to keep a daily record of progress on each objective. For those with access, phone and computer-based applications enhance the ease and accuracy of tracking. The primary focus of provider-patient discussions of progress should be on behavioral objectives, not outcomes.
Accurate knowledge of current behavior is key to setting behavioral objectives for nutrition and exercise. Obtaining a 3-day food record (2 work days and one non-work day) and a baseline for activity (we generally use a week of daily steps measured with a pedometer) provide a solid baseline for setting objectives.
A modest reduction in caloric consumption of around 250 to 500 kcal/day and moderate physical activity on the order of at least 150 minutes a week are the recommended approaches to weight loss.
Reducing calories through decreased food consumption is more effective for weight loss than increasing energy expenditure through physical activity. Box 2 contains a checklist of healthy eating behaviors that can be used to stimulate patients’ thinking about areas in which they might like to make changes. Note that an irregular pattern of eating often underlies unhealthy food choices. For example, staying up late encourages late-night snacking, which in turn can suppress interest in eating breakfast. Eating tends to be deferred to the afternoon or evening, perpetuating the cycle.
|Checklist of Healthy Eating Behaviors|
| Eat meals and snacks at set times to promote health.Examples:
• I will eat breakfast within 1 hour of getting up.
• I will not skip meals.
Eat healthy carbohydrates.
• I will avoid regular soft drinks and choose water or diet soft drinks instead.
• I will eat 5–7 servings of fruits and vegetables every day.
• I will choose whole-grain breads and cereals.
Decrease serving sizes.
• I will keep a record of the food I eat and drink.
• I will know what counts as a serving size.
• When I am eating out, I will share or split an entrée and eat a salad.
Eat less fat and choose healthy fats.
• I will bake, broil, roast, grill, or boil instead of fry food.
• I will have a meatless meal at least once a week.
• I will choose fried or high-fat foods no more than once a week.
• I will drink fat-free or low-fat milk.
• I will use healthy oils (olive oil, canola oil) and buy tub margarine.
Make other healthy choices.
• I will drink plenty of fluids (at least 8 glasses of water or low-calorie fluid per day).
• I will limit how much alcohol I drink. (Women should drink no more than 1 alcoholic drink per day. Men should drink no more than 2 alcoholic drinks per day.)
Unpublished source: Virginia Center for Diabetes Professional Education, University of Virginia; Virginia Diabetes Council.
Physical activity plays an important role in weight maintenance. Higher levels of activity (200 min/week) may be required to prevent long-term weight regain. Box 3 lists ways that patients can become more active. It is worth repeating that the point of these and other suggestions is not to direct patients but to expand their thinking about what might work for them.
|Checklist for Physical Activity|
|Do something that you enjoy.Examples:
• I will take the stairs.
• I will park my car farther away and walk.
• I will walk.
• I will swim or do water exercises.
• I will ride a bike.
• I will use an exercise video.
• I will do yoga.
• Every day
• 10 minutes
• 15 minutes
• 20 minutes
• 30 minutes
• 60 minutes
• I will watch no more than 1 hour of television per day.
• I will spend no more than 2 hours per day on the computer.
Unpublished source: Virginia Center for Diabetes Professional Education, University of Virginia; Virginia Diabetes Council.
Follow-up and Reassessment
Follow-up and reassessment occur during each return visit, following a period of patient efforts to carry out mutually agreed on behavioral objectives. Reassessment focuses on the behavioral records kept by patients as well as on their verbal reports of difficulties and successes. Praise and encouragement are the order of the day. Efforts to initiate behavior change are highly responsive to external positive reinforcement, and the patient will need maximum external reinforcement until new behavior becomes self-sustaining. After review and discussion of patient records, new behavioral objectives or incremental changes in existing objectives are selected by mutual agreement, with the patient taking the lead.
A modest weight loss of 5% to 10% has a positive impact on cardiovascular risk factors and progression of diabetes. Reassure patients that medical goals for weight loss are achievable and worth the effort.
When discussing changes in eating with patients, distinguish dieting from gradual behavioral changes that result in a lasting pattern of healthy eating. Diets are impermanent and run the risk of large weight losses followed by even larger weight gains. Gradual behavioral changes offer the possibility of permanent lifestyle changes.
Prohibiting or demonizing foods is counterproductive. It leads patients to think of food in moral extremes (e.g., “sugar is bad for my diabetes”) rather than along a continuum of nutritional benefit and blood glucose control. Food prohibition also casts the provider as withholding and overly controlling. These traps can be avoided by exploring very small changes that are not perceived as significant losses.
Current nutrition therapy recommendations emphasize a flexible, individualized approach to macronutrient distribution and a carbohydrate-counting meal planning approach for individuals with type 1 diabetes. Patients should be encouraged to emphasize vegetables, fruits, whole grains, legumes, and dairy products as preferred sources of carbohydrate. Recommendations for achieving consistent, appropriate carbohydrate intake at meals are based on controlling postprandial blood glucose (<180 mg/dL 1–2 hours after beginning a meal). Carbohydrate counting and blood glucose pattern management are complicated and time-consuming to teach. Referral to a dietitian for medical nutrition therapy (MNT) or nutrition education through an ADA-recognized diabetes patient education program is recommended.
Stress reduction is important in controlling blood glucose and can also play a role by helping patients achieve a mental focus on their behavior-management efforts. We encourage patients to sit calmly for a period of 5 to 10 minutes each day, focusing on slow deep breathing and muscle relaxation. Activities such as yoga or tai chi also reduce stress and support awareness of body and mind. Box 4 contains suggestions for coping behaviors that may be useful to patients in dealing with stress.
|Checklist of Coping Behaviors|
• Talk about how you feel to people you trust.
• Decide one small way to change your mood or old habit, and do it.
• Write down 10 good things about your life and think about and appreciate them.
• Organize your day with a “To Do” list.
• Learn how to relax through yoga, meditation, biofeedback, tai chi, deep breathing, or visual imagery.
• Take 30 minutes each day to relax through music, yoga, bath, writing, etc.
• Take time to have fun every day by exploring a new interest, watching a funny movie, going shopping, playing with a pet, etc.
• Get in touch with your spiritual side to help you feel better about yourself.
• Keep a stress diary to see what triggers your stress and discover better ways to react.
• Exercise every day to help you focus your energy on a more positive path.
• Keep your sleep cycle as regular as possible.
• Develop a favorite hobby.
Unpublished source: Virginia Center for Diabetes Professional Education, University of Virginia; Virginia Diabetes Council.
Eventually, most patients with T2DM require drug treatment, often with multiple agents (combination therapy). Progressive insulin secretory loss probably is the primary explanation for the need to advance treatment. A resultant general rule with all therapies is add, don’t switch, but it is important to remember that lifestyle modification should always be part of the therapy if possible. Table 2 lists major types of pharmacotherapeutic interventions with their usual hemoglobin (Hb) A1c lowering, balance of preprandial versus postprandial effects, and some comments on their actions and side effects. Table 3 lists classes of drugs, commonly used agents, and typical doses.
Overview and Characteristics of Therapy Interventions in T2DM
* Older drugs may be less effective in well-controlled patients.
† Rapid acting secretagogues may have less fasting and more early postprandial effects.
‡ Metformin dosing: Adjust for CKD stage 3a (45–60 eGFR); watch closely but continue, and in 3b (30–44 eGFR), reduce dose to ½ usual or less and check eGFR every 3 months.
§ Although risk of pancreatitis exists, unclear if increased. Risk of pancreatic cancer not proven and based on controversial data.
Dosing Used for Noninsulin Agents
Ping litazonc (Actos)
Metkirmin IR (Gliictipi me)
Natcg lintels (Starlix)
Sulforiylureas (Second Geix:ration)
Glipizic4e IR (Gltcotrol)
Glipiziclc ER (Glucotrol XL)
Glirrc• piridc (Aiivtrv, l)
Clvbraic4c• (Cly sc•)
Exeixaticle (Bvc )
Excixatide QW Byckzcon
Limy liidcle (Victoza)
Sitagliptin (Jwiiv ia)
Snxngliptin (Ongiy zu)
Litxig liphn (Tra‹djenla)
Alog lipbia (Nesiria)
Pramliiib‹:lc• ( ›y rnlin)
Bile Acid Seqt×:strant
Brorrcic riptine (Cy closet)
Dapngliiloxin” (F ga)
15, 3t1, 45 up
2, 4, 8 rrg
25,50,100 mg ac
5Otl, b5U, 1000 rr(;*
500, 7SU, 1000 rrg
511—120 mg ac
0.5-—4 rrg ac
2.5 J0 mg
5, 10 ¿tg
0.6. 1.2, 1.8 rrg
30, 50 rrg
0.75, 1.5 rrg
100, :›0, 25 rug’
5, 2.:› rrg
25, 12.5, 6.25 mg
15, 3O, 45, 6tJ, 90, 120 ¿ig’
| 0.8–4.5 mg’
100, 300 rrg
5, 10 mg
10, 25 rrg
* Also available as a liquid preparation 500 mg/5 mL.
† Dose adjusted for renal function.
‡ Pens come in range for type 1 (15–60 μg) and type 2 (60–120 μg).
~ Restriction on use lifted as CVD risk not clearly increased.
§ Take with food within 2 h of awakening.
$ All of SGLT2 drugs use lower doses with moderate renal dysfunction and are contraindicated in severe renal dysfunction.
** Powder reconstitutes in the pen before use with twist.
Recently the ADA and European Association for the Study of Diabetes (EASD) updated a joint consensus algorithm on controlling hyperglycemia in T2DM. In our practice, we similarly initiate behavioral self-management with and sometimes without medication. Metformin is the first medication usually started unless there are contraindications or intolerance. Commonly, ineffective early attempts by physicians to change behavior (e.g., giving general advice) lead to abandonment of this therapy. Referral to an ADA Recognized diabetes education program is a more efficacious alternative. A second oral medication may be initiated if patients cannot achieve glycemic goals. Commonly, we favor insulin secretagogues, especially glimepiride (Amaryl) or extended-release glipizide (Glucotrol XL), for their relatively low risk of hypoglycemia, convenient once-daily dosing, and low expense, or an oral incretin drug. An alternative treatment strategy for heavier, more insulin- resistant patients is use of a thiazolidinedione, pioglitazone, effectively a dual insulin-resistance strategy (see Thiazolidinediones).
More reliably effective is the use of basal insulin treatment as a second agent to achieve control, although it is less accepted by many patients. Insulin initiation should be preceded by an open discussion of the patient’s attitudes, beliefs, and possible fears regarding insulin. Insulin therapy should never be used as a threat or possible negative consequence for failure to carry out behavioral management. Many patients associate insulin with serious diabetes complications and mortality. A positive attitude about the value of insulin therapy and its natural presence and essential role in the body, along with reassurance that insulin can prolong life and improve its quality, can help to reduce initial fears enough to begin. Availability of many non- insulin medications has often moved insulin to later in the sequence but it can be used at any time.
Self-demonstration of injection technique using saline is also useful in overcoming fear of injections. Improvement in blood glucose control with insulin generally makes patients feel better, which further reinforces its perceived value. Use of insulin pens may increase acceptance of insulin treatment, patient convenience, and dosing accuracy.
It should be noted that an alternative algorithm for glycemic control therapy is proposed by the American College of Endocrinology. A patient-centered approach with emphasis on safely achieving goals and including patient choices and preferences is increasingly emphasized in both ADA and AACE guidelines.
Oral Agents Secretagogues
These drugs enhance insulin secretion. There are first- and second- generation oral sulfonylureas; the latter are most commonly used. They are inexpensive, are moderately effective, and often can be dosed once daily. First-generation agents such as tolbutamide, chlorpropamide (Diabenese), and tolazamide (Tolinase) are less often used than the second-generation agents glyburide (Diabeta, Glynase), glipizide (Glucotrol), and glimepiride (Amaryl). Glyburide should not generally be used in elderly patients or those with renal disease due to hypoglycemia risk.
The dose-response characteristics of sulfonylureas suggest that one half the approved maximum dose achieves maximum HbA1c lowering, typically 1 to 1.5 percentage points (the latter with poorer baseline control). If the patient is not at goal with half-maximum doses, it is more effective to add a second agent than raise the dose.
Common side effects include hypoglycemia, weight gain of about 2 kg, and, more rarely, hematologic or skin reactions.
The glinides (repaglinide [Prandin] and nateglinide [Starlix]), are more expensive and should be considered for patients who are sulfonylurea allergic, extremely erratic in eating, or at high risk for hypoglycemia.
Metformin is the only available agent in this class. It is useful in both obese and normal-weight T2DM patients. HbA1c lowering is typically about 1.5 percentage points in monotherapy or in combination therapy. Maximum efficacy is achieved with 2000 mg daily. The sustained-release preparation will last 24 hours if given with the evening meal.
Metformin’s hypoglycemic mechanism is primarily by reduction of liver glucose production. It is cleared by the kidney, and the risk of lactic acidosis, a rare side effect with 50% mortality, may be increased in renal dysfunction. The original FDA guidelines suggesting serum creatinine should be less than 1.4 mg/dL in women and less than 1.5 mg/dL in men have largely been supplanted in practice with estimated glomerular filtration rate (eGFR), which should be assessed in all patients. Full doses of metformin appear safe down to eGFR of 45, but checking eGFR every 3 to 6 months is suggested. Between 30 and 44 eGFR, dose should be 1000 mg or less, and eGFR should be checked every 3 months. There may be an increased lactic acidosis risk in patients with congestive heart failure (CHF) or respiratory insufficiency. Intravascular contrast administration should prompt holding the drug for 24 to 48 hours until renal function is confirmed to be adequate. GI side effects are common initially and are dose dependent but wane; they can require gradual titration. Sustained- release preparations have fewer GI side effects. Weight gain is less with this drug than with many others for diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) found that risk of MI and death was reduced, making it a first choice for pharmacotherapy in most patients.
Two thiazolidinediones (TZDs) are used, and they are pioglitazone and rosiglitazone. TZDs increases the sensitivity of muscle tissue and fat to insulin action, probably through adipokines like adiponectin and muscle effects on adenosine monophosphate–activated protein kinase (AMPK), a fuel sensor enzyme, and through effects on glucagon. HbA1c lowering varies, dependent on whether patients are very insulin resistant (central adiposity, often hypertriglyceridemia) and whether there is adequate endogenous insulin secretion (short diabetes duration or secretagogues) or insulin is given.
TZDs can precipitate edema, weight gain due to obesity, and occasionally congestive heart failure even absent a prior heart failure history. It is thus wise to track weight in all patients and limit gains to 5 or 6 pounds. TZDs are contraindicated in patients with heart failue. Pioglitazone studies suggest reduced ischemic risk (stroke or myocardial infarction). TZDs are associated with an increase in fractures in women, which suggests avoiding this medication with high risk of osteoporosis or fragility fractures. The use of pioglitazone is associated with a slightly higher risk of bladder cancer. Sales of rosiglitazone in the U.S. were restricted by the FDA between 2011 and 2013 due to concerns about an increase in heart attacks and death.
These restrictions were lifted in 2013.
Incretins are gut hormones that enhance food-induced insulin secretion. Incretin drugs either are receptor agonists (e.g., exenatide) for glucagon-like peptide-1 (GLP-1), perhaps the most important incretin, or they enhance endogenous levels for both GLP-1 and gastrointestinal insulinotropic polypeptide (GIP).
Exenatide is available as immediate release (Byetta) given twice daily and in once weekly slow release (Bydureon). There is a second available GLP-1 receptor agonist, liraglutide (Victoza), with once daily dosing. Two other agonists, albiglutide and dulaglutide, are approved by the FDA; they are given once weekly. The five incretin agonists increase meal insulin, decrease meal hyperglucagonemia, decrease rate of stomach emptying, and suppress appetite, which may cause a moderate weight loss. They work rapidly on injection. They have substantial GI side effects including nausea, vomiting, and diarrhea in a large minority of patients. Despite this, many patients favor them, probably because the side effects generally wane within weeks and there can be substantial weight loss in some very overweight patients. Typically, exenatide is given in doses of 5 µg twice daily at meals, advancing after a month to 10 µg twice daily. Liraglutide is usually started at 0.6 mg once daily and advanced to 1.2 and then 1.8 mg as needed and tolerated. Patients might report that nausea is more tolerable if they have a little food in their stomach at the time of dosing. Pancreatitis may rarely occur (case reports). Exenatide in a sustained-release once-weekly preparation is embedded into microspheres that permit slow release. The injections require a somewhat larger needle (23 gauge) that is short and well tolerated although somewhat more frequent site reactions and immunogenicity occur with this formulation. Adaptation to nausea seems quicker in longer-acting preparations (once daily or weekly) than in immediate- release exenatide.
Because incretin drugs all have a glucose-dependent insulin secretion and glucagon suppression, there is little risk for hypoglycemia used alone or when they are combined with metformin and TZDs; in contrast hypoglycemia is increased when combined with sulfonylureas or with insulin therapy. HbA1c lowering with exenatide has been 0.9 to 1.1 percentage points, and while albiglutide is similar to exenatide, liraglutide, dulaglutide, or sustained-release exenatide have similar to slightly more efficacy in lowering HbA1c but equal weight effects. Concerns are raised about pancreatitis risk and pancreatic dysplasia, but these remain inconclusive and controversial. Risk of medullary thyroid cancer prevents these drugs from use in patients with that disorder.
Dipeptidyl Peptidase-4 Inhibitors
Dipeptidyl peptidase-4 (DPP-4) is the enzyme that normally rapidly degrades the incretins GLP-1 and GIP to inactive proteolytic products.
Inhibitors of DPP-4 have been shown to enhance GLP-1 and GIP levels to high physiologic levels and thereby reduce HbA1c concentrations, typically about 0.6 to 0.8 percentage points. At this writing, four drugs, sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina) are approved and appear to be similarly effective in recommended doses (see Table 3). Sitagliptin (standard dose 100 mg/d) and alogliptin (standard dose 25 mg/d) are excreted by the kidneys and thus should be given in lower doses (50 mg/d for sitagliptin and 12.5 mg/d for alogliptin) for those with moderate renal insufficiency (eGFR 30–50 for sitagliptin and 30–59 for alogliptin) and further reduced (25 mg/day and 6.25 mg/d, respectively) for those with severe renal dysfunction (GFR<30 mL/min). Saxagliptin is reduced from 5 mg per day to 2.5 mg per day in moderate renal insufficiency (eGFR <50), whereas linagliptin does not need dose adjustment with kidney disease. All have similar actions and probably potential side effects, including pancreatitis.
These drugs are available in combination pills with metformin.
Because DPP-4 inhibitors are oral, they may be preferred to the injectable incretins. The side effects for these drugs are relatively minor, and these drugs cause little nausea, vomiting, or diarrhea. They also do not cause significant weight loss but, like metformin, appear to be weight neutral. Rare but serious allergic reactions such as angioedema and Stevens-Johnson syndrome have been reported in a few patients. Pancreatitis has been observed with this class of drugs rarely. Joint pain is a new uncommon side effect.
Insulin is cosecreted with another beta cell hormone called amylin. The effects of amylin appear to be to help lower glycemia, reduce excess glucagon levels, curb appetite, and possibly reduce the rate of gastric emptying. A synthetic analogue of amylin, pramlintide (Symlin), is available as an injectable agent for treating both T1DM and T2DM as an adjunct to insulin. It lowers HbA1c about 0.5 to 0.7 percentage point. It also appears to have some weight loss effect, typically around 1 to 2 kg. Its action primarily controls glucose postprandially. Nausea and vomiting can occur in patients with either T2DM or T1DM but are worse in T1DM patients who require low doses at first (15 µg or less with meals) and slower titration. Those with T2DM usually start with 60 µg and can usually advance to 90 to 120 µg at meals.
Bile Acid Sequestrants
Colesevalem hydrochloride (Welchol), in either single or divided doses of 3.8 g daily, reduces hyperglycemia compared with placebo in patients with T2DM. A1c reductions range from 0.4% to 0.8% when used alone, with metformin, with sulfonylureas, and when used with insulin and other oral agents. Although this drug has already been approved for treatment of hyperlipidemia, it is now FDA approved also for T2DM. It has the potential, however, to increase triglycerides, and thus baseline fasting lipid values should be obtained and tracked, especially in hypertriglyceridemic patients-use is not recommended when baseline triglycerides exceed 250 mg/dL. There is little justification for its use alone or with thiazolidinediones, but it may be appropriate for some patients with T2DM not at goal on other therapies.
Dopamine Receptor Agonists
Bromocriptine, a dopamine receptor agonist in a rapid release formulation, is a relatively new addition to antidiabetes medications. Although its mechanism of action is not precisely clear, the drug will reduce premeal and postmeal blood sugars without changing insulin levels, which suggests a benefit to insulin action, perhaps through mediation of central nervous system mechanisms. Its side effects are somewhat similar to those of the bromocriptine used for pituitary disease. Nausea is a common initial side effect. Its efficacy is moderate, with HbA1c reductions of 0.5% or slightly more. Its preliminary data suggest a favorable cardiovascular safety profile associated with its use, which is reassuring. Usual starting doses are 0.8 mg once daily with gradual increase based on tolerance of nausea to bromocriptine in higher doses (up to 4.8 mg daily).
Three approved drugs are available; they are canagliflozin, dapagliflozin and empagliflozin. They act as inhibitors of sodium glucose transporters, which lead to a glucose diuresis from the kidney, a unique mechanism of action. This drug is effective in lowering HbA1c up to 1% or more with a relatively low risk of hypoglycemia when used alone or with other drugs such as metformin, but they may cause hypoglycemia when combined with insulin or insulin secretagogues such as sulfonylureas. These drugs may have favorable effects on blood pressure, partly from diuretic effects, and may cause postural hypotension. In monotherapy with these drugs, up to HbA1c reductions of 1% may be seen. Added to metformin, the reduction is 0.5% to 0.75%. Additional benefits may include weight loss of 1.2 to 3.3 kg and a slight reduction in systolic blood pressure of up to 4 to 9 mm Hg, but postural hypotension symptoms or acute kidney injury may occur. Urinary infections are more common, but are treatable.
Candida vulvovaginitis and balanitis are more common with SGLT-2 inhibitors. The usual starting dose is the lowest dose shown in table 3 once daily before the first meal. The dose may be advanced if needed for improving glucose control but only if the eGFR is equal to or greater than 60 mL/min/1.73 m2 for canagliflozin, while for empagliflozin it should not be started if eGFR is < 45 but for values above 45 no dose adjustment is needed, and for dapagliflozin it should not be started if eGFR is < 60 and if > 60 no dose adjustment is needed. For canagliflozin if the eGFR is between 45 and 60, the dose of should not be advanced beyond 100 mg, and if the eGFR is less than 45, the drug should not be used. Frequent monitoring of eGFR is recommended with values less than 60. These drugs should be used with caution in the event of significant renal dysfunction and should not be used in advanced liver or kidney dysfunction. Rarely, ketoacidosis can occur when used with insulin.
Barriers to Insulin Use
Insulin deficiency underlies the genesis of both T1DM and T2DM. Progression of therapy to use of insulin, typically with oral agents in T2DM, also seems predicated on progressive loss of insulin secretion. Nonetheless, it is often started too late, and patients often are in very poor control when this is done. Reluctance by patients and physicians alike might underlie this. Physicians should understand that exogenous insulin in T2DM is needed, does not negatively alter life quality, and is more likely to achieve therapeutic targets. Moreover, exogenous insulin does not worsen insulin resistance, does not cause excess cardiovascular disease, and has a low frequency of severe hypoglycemia, especially when used relatively early in the disease.
Table 4 lists common insulin preparations and some notes about kinetics and timing.
Abbreviation: NPH = neutral protamine Hagedorn.
* Bedtime dosing may be preferred for some patients, especially those on low doses.
† Should not be mixed with other insulins or used in the same syringe that other insulin has been in.
# Advance dose no faster than every 3–4 days, slightly higher doses may be needed compared to U-100 insulin glargine.
Starting Insulin: Use of Basal Insulin in Type 2 Diabetes
How should insulin be started? Practitioners should use temporary insulin for patients whose glycemia is initially poorly controlled or when patients temporarily have worse control due to illness or medications, such as glucocorticoids. It is unwise to use insulin as a threat because it creates a sense of personal failure and dread of insulin use. When therapy progresses but there is failure to achieve glycemic goals after one or two oral medications, use of basal insulin is often the best way to achieve euglycemia, especially if patients are much more than 1 percentage point from HbA1c goal (< 7%).
The Treat-to-Target Trial offers a good example of how to initiate insulin therapy. In this study, as often in our practice, patients start with a basal insulin either with NPH insulin or insulin glargine (Lantus). Insulin detemir (Levemir) represents another long-acting insulin analog option to be used similarly. Insulin is instituted as 10 U once daily, commonly in the evening near bedtime, followed by weekly increases of between 2 and 8 units depending on proximity to glucose goals, focusing on the fasting glucose.
This strategy is sometimes called the fix the fasting first rule. Average doses in that study were around 45 to 50 units for patients whose BMI was about 31 kg/m2. An alternative initial dosing might be 0.2 U/kg body weight, but whatever the starting dose, a forced titration guided by patient self-monitoring with clear communication of target fasting glucose (90–130 mg/dL), size of increment (or decrement in case of hypoglycemia; usually 10%–20% of dose), and frequency of change (every 3–7 days) is necessary to get most patients to overall glycemic (HbA1c) goal. This strategy is referred to as pattern management. The intent is to use monitoring to adjust the insulin dose likely to affect the fasting glucose for basal insulin therapy. NPH and detemir usually can be used once daily, typically at bedtime. Patients using glargine may choose any time of the day as long as it is reasonably consistent, usually within an hour. Occasionally, twice-daily NPH or detemir is used. The new U-300 insulin glargine may be helpful in reduction of overnight hypoglycemia, as it has a flatter kinetic profile and longer duration of action.
When and How to Add Meal Insulin
At some point, basal insulin therapy alone may be insufficient for glycemic control for T2DM patients. Usually this is a consideration in patients whose HbA1c values are over 9% to 9.5% or where the fasting goal is met but HbA1c or daytime glycemia remains elevated. The need for meal insulin is particularly likely to occur with larger meals, such as supper. Diagnostically, what is important is to have patients check either both before and after large meals or, if they are unwilling to check frequently, simply check about 2 to 3 hours after meals. Self- monitored glucose values that exceed even minimum postprandial glycemic guidelines (<180 mg/dL) indicate the need for meal insulin.
A common mistake made in practice is to treat fasting hyperglycemia only with increases in basal insulin, when in some patients, the cause is overeating or lack of meal insulin the previous evening. This can be discerned by observing the pattern of glycemia, with lows often between meals or overnight and highs occurring after meals or at bedtime.
Fixed-Ratio Combined Insulins
A commonly employed strategy is to use fixed-ratio combination short-acting (either regular or rapid analog) insulin combined with intermediate insulin (NPH or neutral protamine modified rapid analog that mimics NPH timing). Examples of these preparations include 70/30 NPH and regular insulin, 75/25 neutral protamine lispro and lispro insulin (Humalog), and 70/30 neutral protamine aspart and aspart insulin (Novolog). These have the advantage of being able to achieve control very conveniently in T2DM patients who have quite poor control (HbA1c of 9.5% or more) with a simple twice-daily injection regimen. They also offer the advantage of greater dosing accuracy, especially when used with insulin pens. Important to the success of these formulations is consistent eating and carbohydrate intake with meals. Unfortunately, when such consistency is not advised or followed, patterns of glycemia can be erratic and hypoglycemia can be significantly increased due to both components of the combination. Patients who skip meals are poor candidates for such treatments and should either switch to individual dosing of an insulin mixture or, even safer, use a basal bolus insulin regimen.
Adults with Type 1 DM
A significant minority of patients with a diagnosis of T2DM actually have a late onset of T1DM and typical autoimmunity (IA-2 antibodies, GAD-65 antibodies, and insulin antibodies). The diagnosis should certainly be suspected in patients who rapidly fail combination oral agent therapy. Nonobese body habitus, marked weight loss, extremely elevated glucose values, or a family or personal history of autoimmune disease (e.g., Hashimoto’s or Graves’ thyroid problems) should lead to diagnostic evaluation for such signs of autoimmunity. T1DM patients need combined mealtime and basal insulin therapy.
Although it is tempting to do so in a convenient fashion with combined preparations such as those with analogue fixed ratios, it usually is far preferable to use a better basal insulin, such as glargine or detemir combined with a rapid-acting analogue (separately injected) before meals. Sometimes an insulin pump is the best way for patients who have frequent hypoglycemia or marked variability to achieve good glycemic control safely. T1DM patients should preferably be seen by an endocrine specialist or other practitioner with extensive experience in T1DM management. Ready access to diabetes educators is an important key to success with both T1DM and T2DM.
Adults with Type 2 DM
Many T2DM patients eventually need mealtime insulin. For those on basal insulin alone, incretin mimetics1 can be successfully used for meal-time control, because they effectively lower prandial hyperglycemia. If exenatide is used, then additional injections will be required at the two major meals of the day. If using an incretin- enhancer drug such as sitagliptin, injections are not required. This approach is useful with incretin agonists exenatide or liraglutide in patients who need to lose weight, who gain considerable weight with meal insulin, or who experience poor control despite attempts to regulate meal glycemia with short-acting insulins. Recent studies suggest possible benefit of combining long acting basal insulins with incretin receptor agonists.
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