Treatment of T2DM

Glycemic Management in Type 2 Diabetes

The Comprehensive Care Plan

Every patient with documented type 2 diabetes (T2D) should have a comprehensive care plan (CCP), which takes into account the patient’s unique medical history, behaviors and risk factors, ethnocultural background, and environment. The ultimate goal of the CCP is to reduce the risk of diabetes complications without jeopardizing patient safety. To achieve this goal, the CCP should include the following components:1

The multidisciplinary team typically oversees the medical management of T2D, including the prescription of antihyperglycemic therapy and the delivery of diabetes self-management education (DSME). DSME is used to educate the patient on the components of therapeutic lifestyle changes, namely medical nutritional therapy (MNT) and physical activity. Each patient’s understanding of and participation in the CCP is essential to its success.1

Therapeutic Lifestyle Change

The components of therapeutic lifestyle change include:1

  • Healthful eating
  • Sufficient physical activity
  • Sufficient sleep
  • Avoidance of tobacco products
  • Limited alcohol consumption
  • Stress reduction

Nutritional Medicine

Nutritional medicine for diabetes involves counseling about general healthful eating, MNT, as well as nutritional support when appropriate (eg, in patients receiving enteral or parenteral nutrition in which medications provided for glycemic control must be synchronized with carbohydrate delivery; see AACE Inpatient Glycemic Control Resource Center for more information).1

Healthful Eating

Either the physician or a registered dietitian (RD) should discuss healthful eating recommendations in plain language at diagnosis of T2D and then periodically during follow-up office visits (Table 1). These recommendations are suitable for the general population, including people without diabetes, and focus on foods that can promote health vs foods that may promote disease or complications. Discussions should cover specific foods, dishes, meal planning, grocery shopping, and dining-out strategies.1

Table 1. AACE Healthful Eating Recommendations1

Topic

Recommendation

General eating habits

  • Regular meals and snacks; avoid fasting to lose weight
  • Plant-based diet (high in fiber, low calories/glycemic index and high in phytochemicals/antioxidants)
  • Understand Nutrition Facts Label information
  • Incorporate beliefs and culture into discussions
  • Informal physician-patient discussions
  • Use mild cooking techniques instead of high-heat cooking

Carbohydrate

  • Explain the 3 types of carbohydrates: sugars, starch, and fiber and the effects on health for each type
  • Specify healthful carbohydrates (fresh fruits and vegetables, pulses, whole grains); target 7-10 servings per day
  • Lower-glycemic index foods may facilitate glycemic control, but there is insufficient evidence to support a formal recommendation to educate patients that sugars have both positive and negative health effects
    • Glycemic index score <55 out of 100:
      • Multigrain bread
      • Pumpernickel bread
      • Whole oats
      • Legumes
      • Apple
      • Lentils
      • Chickpeas
      • Mango
      • Yams
      • Brown rice

Fat

  • Specify healthful fats
    • Low mercury/contaminant-containing nuts
    • Avocado
    • Certain plant oils
    • Fish
  • Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and transfat
  • Use no- or low-fat dairy products

Protein

  • Consume most protein in foods with low saturated fats (fish, egg whites, beans); there is no need to avoid animal protein
  • Avoid or limit processed meats

Micronutrients

  • Routine supplementation is not necessary
    • A healthful-eating meal plan can generally provide sufficient micronutrients
  • Supplementation is recommended for patients at risk of insufficiency or deficiency
  • Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended for glycemic control

Medical Nutritional Therapy (MNT)

MNT involves a more detailed discussion of calories, grams, and other metrics, as well as intensive implementation of dietary recommendations aimed at optimizing glycemic control and reducing the risk for complications. Recommendations should be personalized, and in general, evaluation and teaching should be conducted by an RD or knowledgeable physician. In areas underserved by RDs, physicians should take on more responsibility with nutritional counseling and reinforcement of healthful eating patterns during patient encounters.1

Key MNT recommendations include the following:1

  • Consistency in day-to-day carbohydrate intake
  • Adjusting insulin doses to match carbohydrate intake (eg, use of carbohydrate counting)
  • Limitation of sucrose-containing or high-glycemic index foods
  • Adequate protein intake
  • “Heart-healthy” diets
  • Weight management
  • Exercise
  • Increased glucose monitoring

All patients should be advised how to achieve and maintain a healthful weight, corresponding to a normal body mass index range between 18.5 to 24.9 kg/m2. Overweight individuals with type 2 diabetes should strive for a 5% to 10% reduction in weight and should avoid weight gain. Recommendations should be personalized on the basis of a patient’s specific medical conditions, lifestyle, and behavior. Patients unable to maintain a healthy weight on their own should be referred to an RD or weight-loss program that has a proven success rate.

Physical Activity

Many studies have shown that regular physical activity improves glucose control in persons with T2DM.2-7 Physical activity is also a main component in weight loss and maintenance programs and is particularly important in the weight maintenance phase.1,8 T2DM patients’ physical activity regimens should consist of the following:1,8,9

  • 150 minutes of moderate-intensity aerobic exercise such as brisk walking or its equivalent, spread out over at least 3 days during the week, with no more than 2 consecutive days between bouts of aerobic activity
  • Moderate to vigorous resistance training 2–3 days per week
  • Daily, unstructured physical activity such as walking at least 10,000 steps over the course of the day

Patients should be advised that any physical activity is better than none, and that they should make every effort to increase their activity level. Unstructured activities include walking up or down stairs instead of using elevators, using parking spaces farther from building entrances, and the like. The use of pedometers with a goal of 10,000 steps per day can help patients improve their daily activity level.10 All physical activity routines should include flexibility and strength-training exercises with aerobic exercise.1,8 Supervised physical activity (eg, with a personal trainer) may lead to greater adherence to an exercise program and improved blood glucose control than exercise training without supervision.2

To help motivate patients, it may be useful to remind them of the following benefits of increased physical activity:1,4,8

  • Reduce all-cause and CV mortality
  • Reduce weight, blood pressure, and LDL-C, especially when combined with dietary changes aimed at weight loss
    • Up to 60 minutes per day may be required when relying on exercise alone for weight loss
  • Improve insulin action, blood glucose control, and fat oxidation and storage in muscle
  • Decrease the risk of falls and fractures due to enhanced muscle mass (especially resistance training)
  • Improve functional capacity and health-related quality of life, as well as reduce symptoms of depression

Additional key points to remember when counseling patients on exercise are as follows:1

  • Patients must be evaluated initially for contraindications and/or limitations to increased physical activity.
  • An exercise prescription should be developed for each patient according to both goals and limitations.
  • Additional physical activity should be started slowly and built up gradually.

Antihyperglycemic Pharmacotherapy

The goal of glycemic treatment of persons with T2DM is to achieve clinical and biochemical targets with as few adverse consequences as possible.1 Both the 2009 AACE/ACE Diabetes Algorithm for Glycemic Control and the 2012 American Diabetes Association/European Association for the Study of Diabetes Position Statement emphasize this fundamental concept. These guidelines share the following key recommendations regarding the treatment of hyperglycemia:11,12

  • Glycemic goals should be individualized based on patient characteristics.
  • Antidiabetic treatment should be promptly intensified to maintain blood glucose at individual targets.
  • Combination therapy will be necessary for most patients.
  • Selection of agents should be based on individual patient medical history, behaviors, and risk factors, ethnocultural background, and environment.
  • Insulin is eventually necessary for many patients.
  • Self-monitoring of blood glucose (SMBG) is a vital tool for day-to-day management of blood sugar in all patients using insulin and many patients not using insulin.

Table 2 lists the antihyperglycemic agents available for the treatment of T2DM.

Table 2. Antihyperglycemic Agents12,13

Class

Primary Mechanism of Action

Agent

Available as

α-Glucosidase inhibitors

  • Delay carbohydrate absorption from intestine

Acarbose

Precose or generic

Miglitol

Glyset

Amylin analog

  • Decrease glucagon secretion
  • Slow gastric emptying
  • Increase satiety

Pramlintide

Symlin

Biguanide

  • Decrease HGP
  • Increase glucose uptake in muscle

Metformin

Glucophage or generic

Bile acid sequestrants

  • Decrease HGP?
  • Increase incretin levels?

Colesevelam

WelChol

Dipeptidyl peptidase 4 (DPP-4) inhibitors

  • Increase glucose-dependent insulin secretion
  • Decrease glucagon secretion

Linagliptin

Tradjenta

Saxagliptin

Onglyza

Sitagliptin

Januvia

Dopamine-2 agonist

  • Activates dopaminergic receptors

Bromocriptine

Cycloset

Glinides

  • Increase insulin secretion

Nateglinide

Starlix or generic

Repaglinide

Prandin

Glucagon-like peptide 1 (GLP-1) receptor agonists

  • Increase glucose-dependent insulin secretion
  • Decrease glucagon secretion
  • Slow gastric emptying
  • Increase satiety

Exenatide

Byetta

Exenatide XR

Bydureon

Liraglutide

Victoza

Insulin

 

 

 

    Basal

  • Increase glucose uptake
  • Decrease HGP

Detemir

Levemir

Glargine

Lantus

Neutral protamine Hagedorn (NPH)

Generic

    Prandial

Aspart

NovoLog

Glulisine

Apidra

Lispro

Humalog

Regular human

Humulin

    Premixed

Biphasic aspart

NovoLog Mix

Biphasic lispro

Humalog Mix

Sulfonylureas

  • Increase insulin secretion

Glimepiride

Amaryl or generic

Glipizide

Glucotrol or generic

Glyburide

Diabeta, Glynase, Micronase, or generic

Thiazolidinediones

  • Increase glucose uptake in muscle and fat
  • Decrease HGP

Pioglitazone

Actos

Rosiglitazone*

Avandia

Single-tablet combination products

Metformin + DPP-4 inhibitor

Linagliptin

Jentadueto

Saxagliptin

Kombiglyze XR

Sitagliptin

Janumet, Janumet XR

Metformin + glinide

Repaglinide

Prandimet

Metformin + sulfonylurea

Glipizide

Metaglip and generic

Glyburide

Glucovance and generic

Metformin + thiazolidinedione

Pioglitazone

ACTOplus Met

Rosiglitazone*

Avandamet

Thiazolidinedione + sulfonylurea

Pioglitazone

Duetact

Rosiglitazone*

Avandaryl

Abbreviation: HGP, hepatic glucose production.
*Use restricted due to potential for increased risk of myocardial infarction (MI).

All currently available oral glucose-lowering monotherapy agents are more or less similar in their glucose-lowering potency.14,15 The apparent greater efficacy of agents brought to market in the past, compared with the efficacy of newer agents, is probably because of higher baseline glucose levels.15 For this reason, the choice of therapeutic agents should be based on their differing metabolic actions and adverse effect profiles as described in Table 3 and the 2009 AACE/ACE Diabetes Algorithm for Glycemic Control.

Table 3. Summary of Key Benefits and Risks of Medications13

Detailed discussion of all these agents can be found in the 2009 AACE/ACE Algorithm and the 2012 ADA/EASD Position Statement. However, AACE would emphasize a few key points:

  • The AACE algorithm outlines treatment choices on the basis of the current A1C level.
  • Most patients with an initial A1C level greater than 7.5% will require combination therapy using agents with complementary mechanisms of action.
  • Antihyperglycemic agents may be broadly categorized by whether they predominantly target FPG or PPG levels (see Table 3).
    • These broad categories can aid in therapeutic decision-making.
    • The choice of whether to target FPG or PPG should be based primarily on the individual patient’s glycemic profile obtained by self-monitoring of blood glucose (SMBG).
  • Intensification of pharmacotherapy requires glucose monitoring and medication adjustment at appropriate intervals when treatment goals are not achieved or maintained.
  • In developing its algorithm, AACE prioritized the choice of medications as follows:
  1. Minimizing the risk and severity of hypoglycemia
  2. Minimizing the risk and severity of weight gain
  3. Efficacy, including relative effects on FPG and PPG
  4. Simplicity and anticipated degree of patient adherence
  5. Cost

Insulin Therapy for T2DM

Both AACE and the ADA/EASD recommend insulin for patients with T2DM when noninsulin antihyperglycemic therapy fails to achieve the patient’s individual glycemic control target or when a patient, whether drug naive or not, has symptomatic hyperglycemia (A1C ≥9.0%).12,13

Long-acting basal insulin is generally the initial insulin choice, and the insulin analogues glargine and detemir are strongly preferred over human NPH insulin because they have relatively peakless time-action curves and a more consistent effect from day to day, resulting in a lower risk of hypoglycemia. Degludec, a new ultra-long–acting basal insulin, is currently undergoing review by the U.S. Food and Drug Administration (FDA). In general, AACE recommends implementing basal insulin therapy as follows:12,13

  • Start with small arbitrary dose (usually 10 U or 0.1-0.2 U/kg per day)
  • Slowly titrate by small increments (1-3 U) every 2-3 days until fasting plasma glucose (FPG) reaches the desired target (80-110 mg/dL for most patients)
  • Decrease dosage if FPG declines below a specified low threshold

Basal insulin is usually added to existing noninsulin therapy, and many antihyperglycemic agents are approved for use with insulin: DPP-4 inhibitors, glinides, GLP-1 receptor agonists (but not exenatide XR), metformin, pramlintide, sulfonylureas, and TZDs. The following limitations should be considered when combining insulin with noninsulin agents:1

  • The risk of hypoglycemia is increased when combining insulin with sulfonylureas, glinides, DPP-4 inhibitors, and GLP-1 receptor analogues.
    • Sulfonylureas and glinides should be discontinued if starting prandial insulin.
    • GLP-1 receptor analogues and DPP-4 inhibitors have not been studied with prandial insulin.
  • Using insulin with TZDs may increase the risk of weight gain, edema, and congestive heart failure.

When A1C levels remain high despite optimal control of FPG with basal insulin plus noninsulin agents, prandial insulin should be added:12,13

  • Rapid-acting insulin analogues are preferred over regular human insulin because they have a more rapid onset and offset of action and are associated with less hypoglycemia.
  • Premixed insulin analogue therapy may be considered for patients in whom drug regimen adherence is an issue; however, these preparations lack component dosage flexibility and may increase the risk for hypoglycemia compared with basal insulin or basal-bolus insulin.
  • Basal-bolus insulin therapy is flexible and is recommended for intensive insulin therapy.

This approach (ie, transitioning to insulin after noninsulin agents fail to maintain glycemic targets) is supported by the recently published results of the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial. This 6-year study, which included over 12,000 patients, compared the use of insulin glargine with standard care in patients with cardiovascular risk factors plus either prediabetes or recent-onset T2DM (mean T2DM duration at baseline: 5 years). In the glargine group, the insulin dose was titrated to achieve a dose of ≤95 mg/dL, while the standard care group was treated according to local guidelines and the investigator’s clinical judgment. Insulin use in the prediabetic patients did reduce the incidence of T2DM (see detailed discussion in Prediabetes), but there was no difference in cardiovascular outcomes between treatment groups after 6 years. Median FPG and A1C levels were lower in the glargine group, but the incidence of hypoglycemia and weight gain were modestly increased. The study authors concluded that there was no reason to change the standard of care for T2DM.16

Pipeline Products

Several new classes of agents are under investigation for the treatment of T2DM, and some new agents within existing classes may represent improvements over currently available options.17 The listing in Table 4 should be considered representative and not necessarily all-inclusive.

Table 4. Antidiabetic Agents Under Investigation

Class
Phase of Development

Agents

Description

Dual peroxisome proliferator activated receptor
α-γ (PPARα-γ) agonist
Phase 3

Aleglitazar

Improve insulin sensitivity in the periphery as well as lipid profiles; approved agents may be expected to reduce both cardiovascular risks and the risk of diabetes complications17

GLP-1 receptor agonists
Phase 3

Albiglutide
Dulaglutide
Lixisenatide

Effects likely to be similar to those of currently available GLP-1 receptor agonists

Insulin
Phase 3

Degludec

Ultra-long-acting basal insulin (half-life ~25 hours) with low within-subject variability and potential for reduced incidence of hypoglycemia18-20

Degludecplus

Premixed insulin containing degludec plus aspart, providing control of both fasting and postprandial glucose21,22

Sodium-dependent glucose cotransporter 2 (SGLT-2) inhibitors
Phase 3

Canagliflozin
Dapagliflozin
Empagliflozin
Tofogliflozin

Act in the kidney, reducing hyperglycemia by inhibiting glucose reabsorption into the bloodstream from the renal filtrate; urinary excretion of glucose increases as a result23,24

Salicylates
Phase 3

Salsalate

Generically available anti-inflammatory medication currently approved for treatment of arthritis; inhibits activity of NF-κB, an inflammatory factor25

11β-Hydroxysteroid dehydrogenase type 1 (11βHSD-1) inhibitors
Phase 2

INCB13739
RG4929

Inhibit 11βHSD-1 mediated conversion of low-activity cortisone to cortisol, which is primarily produced in the liver and adipose tissue; may reduce stress-induced obesity, improve insulin sensitivity, enhance insulin-secretory responsiveness, and improve glucose tolerance in patients with metabolic syndrome and/or T2DM17

Several other classes are under preclinical investigation, with results available only from animal studies.26 These include:

  • Glycogen phosphorylase inhibitors
  • Glucokinase activators
  • G protein–coupled receptor 119 (GPR119) agonists
  • Protein tyrosine phosphatase (PTP) 1B inhibitors
  • Glucagon receptor antagonists

Technology and Devices in T2DM

Technological advancements over the past decades have led to a variety of devices for use in the treatment of diabetes:

For complete descriptions of the devices and accompanying technology themselves, click on the links above.

SMBG in T2DM

Noninsulin Users. Each patient should be introduced to an SMBG program upon diagnosis, along with the start of medical therapy.13 T2DM patients not using insulin may benefit from SMBG, especially to provide feedback about the effects of their lifestyle and pharmacologic therapy, as well as alert them to episodes of hypoglycemia (if on hypoglycemic oral agents such as sulfonylureas or meglitinides).

Several studies have shown that SMBG has a positive impact on glycemia in T2DM, especially when the results are used to modify behavior and/or pharmacologic treatment.29-31 Testing frequency should be personalized, but SMBG results should be used to inform decisions about whether to target FPG or PPG for any individual patient.1,13,32

Insulin Users. AACE and the ADA both recommend that SMBG should be performed by all patients using insulin. AACE recommends testing a minimum of twice daily (ADA: at least 3 times daily) and before any injection of insulin.1,32 More frequent SMBG after meals or in the middle of the night may be required for insulin-taking patients with frequent hypoglycemia, patients not at A1C targets, or those with symptoms.1

CSII in T2DM

CSII is recommended mainly for patients with type 1 diabetes mellitus (T1DM), but patients with advanced T2DM who are absolutely insulin-deficient, take 4 or more insulin injections a day, and assess their blood glucose levels 4 or more times daily are candidates for CSII. These patients must also be motivated to achieve tighter plasma glucose control and be intellectually and physically able to undergo the rigors of insulin pump therapy initiation and maintenance. Additional requirements are:1,27

  • Frequent SMBG testing
  • Mastery of carbohydrate counting, insulin correction, and adjustment formulas
  • Ability to troubleshoot problems related to pump operation and plasma glucose levels
  • Stable life situation
  • Frequent contact with members of their healthcare team, in particular their pump-supervising physician

Surgery as a Treatment Approach for T2DM

Studies have confirmed that bariatric surgery can reverse existing T2DM.33-38 Some procedures, such as the Roux-en-Y gastric bypass, also have a positive effect on various neuroendocrine hormones, which may contribute to a sustained benefit.33,34 A recent trial examined the effects of surgery in 150 obese patients with uncontrolled T2DM (baseline A1C 9.2%) who were randomly assigned to medical therapy for T2DM alone or medical therapy plus Roux-en-Y gastric bypass or sleeve gastrectomy. After 12 months, only 12% of the medical-therapy group had an A1C ≤6.0% versus 42% in the gastric-bypass group (P=0.002) and 37% in the sleeve-gastrectomy group (P=0.008). While medical therapy alone reduced mean A1C to 7.5%, A1C was 6.4% in the gastric-bypass group (P<0.001) and 6.6% in the sleeve-gastrectomy group (P=0.003) after 1 year. All groups also lost weight, with significantly greater losses occurring in the surgical groups (-29.4±9.0 kg for gastric bypass and -25.1±8.5 kg for gastrectomy vs -5.4±8.0 kg for medical therapy; P<0.001 for both comparisons).35

AACE recommends bariatric surgery only for obese patients: laparoscopic-assisted gastric banding for patients with a body mass index (BMI) >30 kg/m2 or Roux-en-Y gastric bypass for those with a BMI >35 kg/m2. Patients with T2DM who undergo Roux-en-Y gastric bypass must have meticulous metabolic postoperative follow-up because of a risk of vitamin and mineral deficiencies and hypoglycemia.1

Safety and Tolerability

Safety—particularly the risk of hypoglycemia—should be the primary concern when choosing an antidiabetic therapy. This is the first principle behind the 2009 AACE/ACE Glycemic Control Algorithm as well as the 2012 ADA/EASD Position Statement.

Table 3 lists the major safety risks associated with currently available antidiabetic agents. While individual agents may have contraindications or carry increased risks for specific populations, in general, hypoglycemia and weight gain are the primary limiting factors in diabetes treatment.

Hypoglycemia

Hypoglycemia is the main limiting factor in diabetes therapy and stems from an imbalance among insulinogenic therapy, food intake, physical activity, organ function (gluconeogenesis), and counterregulation with glucagon and/or epinephrine (hypoglycemia-associated autonomic failure). Hyperinsulinemia, increased alcohol intake, starvation, and organ failure may be aggravating factors for hypoglycemia.1,39,40

Severe hypoglycemia stimulates sympathetic adrenergic discharge, causing arrhythmias or autonomic dysfunction (or both) and has long been recognized to have potential for causing mortality. Intensive glycemic control of T2DM was associated with a 3- to 4-fold increase in hypoglycemia in the ACCORD, ADVANCE, and VADT trials, and in the ACCORD study, iatrogenic hypoglycemia was associated with excess mortality in both the intensively treated group and the conventionally treated group.41-45

In addition to increased mortality, hypoglycemia negatively affects adherence to therapy and quality of life and also contributes to morbidity. Because hypoglycemia causes hunger, it may contribute to weight gain.1 A more serious consequence of recurrent hypoglycemia is brain dysfunction and increased risk of dementia, particularly in elderly individuals.40,46 Older patients are also less likely to recognize the symptoms of hypoglycemia, which can lead to a self-perpetuating cycle of recurrent hypoglycemia and hypoglycemia unawareness.47 Hypoglycemia unawareness is also common in patients who have marked swings in glucose levels and in these patients can be reversed by a period of intensive therapy that dampens glycemic excursions.1

The risk of hypoglycemia increases with the following:46

  • Age
  • Duration of diabetes
  • Duration of insulin therapy
  • Coexisting severe comorbidities
  • Hypoglycemia unawareness

Management of hypoglycemia involves appropriate choice of antihyperglycemic therapy, tailoring of insulin treatment to minimize risks, and patient education in the recognition and treatment of acute hypoglycemia (Table 5).40 It is important to remember that the features listed in Table 5 occur along a continuum, and glycemic thresholds and symptom manifestations may vary widely among individuals.

Table 5. Glycemic Thresholds, Signs, Symptoms, and Treatment of Hypoglycemia1,39,40

Blood Glucose (mg/dL)*

Glycemic Status

Typical Signs/Symptoms

Treatment

~70-110

Normal

 

 

~65-70

Counter-regulatory response: increased glucagon and epinephrine secretion

None

None

~50-60

Mild hypoglycemia

  • Neurogenic: palpitations, tremor, hunger, sweating, anxiety, paresthesia
  • Neuroglycopenic: behavioral changes, emotional lability, difficulty thinking, confusion
  • Consume glucose-containing foods (fruit juice, soft drink, crackers, milk, glucose tablets); avoid foods also containing fat †
  • Repeat glucose intake if SMBG result remains low after 15 minutes
  • Consume meal or snack after SMBG has returned to normal to avoid recurrence

<50

Moderate hypoglycemia

Severe hypoglycemia

  • Severe confusion, unconsciousness, seizure, coma, death
  • Requires help from another individual
  • Glucagon injection, delivered by family member or other close associate
  • Victim should be taken to hospital for evaluation and treatment after any severe episode

*Glycemic thresholds vary among individuals.
†Fat may retard glucose absorption and delay recovery.

Weight Control

As mentioned above, overweight individuals with type 2 diabetes should strive for a 5% to 10% reduction in weight and should avoid weight gain, which can be caused by several antihyperglycemic agents (Table 6).1

Table 6. Antihyperglycemic Agents and Weight Effects

Weight Gain

Weight Neutral or Weight Loss

Glinides
Insulin
Sulfonylureas
Thiazolidinediones

α-Glucosidase inhibitors
Bromocriptine
Colesevelam
DPP-4 inhibitors
GLP-1 receptor agonists
Metformin
Pramlintide

For T2DM patients, most of whom are overweight or obese, the risk of additional weight gain must be balanced against the benefits of the agent itself. Sulfonylureas may negate weight loss benefits of GLP-1 receptor agonists or metformin. Insulin should not be withheld from patients unable to maintain glucose control on noninsulin agents because of the risk of weight gain.1

Evidence for Other Risks Associated with Insulin Use

Preliminary epidemiologic evidence has suggested that insulin may be associated with an increased risk of cancer, although it should also be noted that the risk of some cancers are increased in obese, older individuals (who may be more likely to be taking insulin).48 In the prospective ORIGIN trial, no increased incidence of cancer was observed in >6000 patients receiving glargine over a median trial duration of 6 years.13

Treating T2DM in Special Populations

Pediatric Patients

Once T1DM and monogenic diabetes have been ruled out and a T2DM diagnosis has been definitively established for a child or adolescent, diet and lifestyle modification are always the first treatment choices. However, pharmacologic therapy may be necessary. To date, metformin remains the only oral medication approved by the FDA for use in children with T2DM. Insulin is effective and used widely, alone or in combination with metformin.1

In 2009, the International Society of Pediatric and Adolescent Diabetes published an extensive Clinical Practice Consensus Guideline for the care of diabetes in children, which is available on its Web site.49

Pregnant Women with T2DM

Children born to women with any form of diabetes are at greater risk of developing T2DM themselves. For this reason, women of childbearing potential who have T2DM should receive preconception care and guidance to try to bring A1C levels to ≤6.1%.1 A complete discussion can be found in the Pregnancy and Diabetes section of this Web site.

Elderly Patients

Older adults are more likely to have an increased number of comorbid conditions (eg, frailty, dementia, depression, urinary incontinence) that can complicate their diabetes management. Age-related changes alone can impair vision and kidney function, reduce physical strength and stamina, and increase sensitivity to the side effects of medications.50 In addition, older patients may have impaired counterregulatory mechanisms that make hypoglycemia unawareness and recurrent hypoglycemia more likely.47 All of these factors put older patients at an increased risk for falls.51 In addition, cognitive decline may impair patients’ understanding of and motivation for proper self-care.47,50

While relatively healthy older patients may be treated the same as younger adults with T2DM, less strict glycemic goals and simpler treatment regimens are appropriate for frail patients and/or those who require a large number of medications to control other conditions, in order to minimize drug interactions and other risks of therapy. Elderly patients’ increased risk of falling should be considered before prescribing oral agents that cause hypoglycemia (glinides and sulfonylureas) or thiazolidinediones (which are associated with increased fracture risk).1

Patients Choosing to Fast

Fasting is a common religious practice that can pose a challenge to diabetes management, particularly if the fast occurs over an extended time, such as Ramadan, a holy month of Islam in which all healthy adults consume no food or fluids between sunrise and sunset. The ADA has issued a workgroup report that reviews risks and management recommendations for Ramadan, based on results of the Epidemiology of Diabetes and Ramadan (EPIDIAR) study.52 These recommendations should also be considered for patients who fast for other religious holidays or cultural reasons.

The main risks of fasting are as follows:52

  • Hypoglycemia
  • Hyperglycemia
  • Diabetic ketoacidosis
  • Dehydration and thrombosis

The risk of these outcomes depends on the severity and complications of T2DM according to the categories in Table 7.

Table 7. Risk Categories for Patients Who Fast During Ramadan52

Risk Category

Features

Low

  • Glycemia well-controlled with antihyperglycemic agent that does not cause hypoglycemia (eg, metformin, thiazolidinedione, DPP-4 inhibitor, GLP-1 analogue)
  • Otherwise healthy

Moderate

  • Glycemia well-controlled with glinides

High

  • Moderate hyperglycemia (A1C 7.5%-9.0%), renal insufficiency, cardiovascular complications, and/or other comorbid conditions
  • Living alone, especially if taking sulfonylureas, insulin, or drugs that affect mental activity
  • Elderly, especially with poor health

Very high

  • History of recurrent hypoglycemia, hypoglycemia unawareness, or episode of severe hypoglycemia within 3 months prior to Ramadan
  • Poor glycemic control
  • Ketoacidosis or hyperosmotic hyperglycemic coma within 3 months prior to Ramadan
  • Acute illness or chronic dialysis
  • Intense physical labor
  • Pregnancy

For the management of glycemia during extended fasts, general principles and recommendations are listed below. For a complete discussion, see the ADA Workgroup Report.52

  • Management plan individualized to meet specific patient needs
  • Frequent glucose monitoring; break the fast immediately if SMBG is <60 mg/dL or if <70 mg/dL while taking insulin or secretagogues; also break the fast if hyperglycemia occurs (>300 mg/dL)
  • Healthful eating before and after each fasting period; consider complex carbohydrates prior to fast and avoid ingesting high-carbohydrate, high-fat foods when breaking the fast
  • Avoid excessive physical activity, although normal exercise routines should be maintained
  • Avoid fasting while ill

References

  1. Handelsman Y, Mechanick JI, Blonde L, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17 Suppl 2:1-53.
  2. Balducci S, Zanuso S, Nicolucci A, et al. Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES). Arch Intern Med. 2010;170:1794-1803.
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