Life Style Modification

Weight loss and promote activity have been shown to improve glycemic control.1

 Even modest weight loss (as little as 4 kg) has been shown to improve glucose control.2 Some of the most compelling data come from following patients with diabetes who undergo bariatric surgery.3-6 These procedures, which can result in sustained weight loss of greater than 20 kg may eliminate the need to take medications for diabetes. However, apart from surgery, the rate of observed eventual weight regain has blunted the impact for more modest lifestyle interventions.

Which classes of diabetes medications have been shown to be either weight neutral or cause weight loss?2-7

The following classes of diabetes drugs have all been shown to result in modest weight loss (or, at least, be weight neutral).2,7

Based on the AACE/ACE Comprehensive Diabetes Management Algorithm 2019,8 you feel it would be appropriate to treat her with monotherapy. She is hesitant to take any injection.

3.

What agent would you recommend?8

There is some flexibility in the drug you and the patient may choose. The AACE 2019 Algorithm does recommend three months of monotherapy for patients diagnosed with type 2 diabetes whose initial A1c is less than 7.5%. If the A1c does not get to goal by the end of three months, the patients and providers are encouraged to move to dual therapy. According to the strength of recommendation, most providers would start with metformin. Other top recommended options for monotherapy (in order of the suggested hierarchy of usage outlined in the algorithm) include: GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, and alpha-glucosidase inhibitors. Other agents have been proposed for monotherapy, but are less strongly recommended. These include, the thiazolidinediones (TZDs), sulfonylureas and glinides (also called meglitinides); these last three drug classes mentioned are recommended to only use “with caution.” Since she is hesitant to do any injections, the GLP-1 receptor agonists would not be a choice in keeping with her preferences. Pramlintide (not recommended as first line monotherapy) is also an injectable drug and would, therefore, not fit with her stated preference.

What are the contraindications to metformin therapy?7,9,10

Metformin should not be used in patients predisposed to develop lactic acidosis. Lactic acidosis is a rare, but potentially fatal complication of treatment with this drug. Its use is contraindicated in patients with decompensated congestive heart failure (CHF).7 (It was formerly contraindicated for all patients with a history of heart failure, but in a large retrospective trial of elderly patients with type 2 diabetes mellitus and CHF, the patients treated with metformin had a lower mortality [33%] than those treated with sulfonylureas [52%].9) Metformin should not be used in patients with severely impaired renal function (estimated glomerular filtration rate [GFR] less than 30 mL/min/1.73 m2).10 Others in whom this medication is contraindicated are patients with liver failure, heavy alcohol use, or in patients undergoing major surgery. Remember to warn patients on metformin that this drug should be stopped whenever a study requiring iodinated contrast is needed and not restarted until 48 hours later if the renal function permits.7


Her creatinine is 0.9 mg/dL and her estimated glomerular filtration rate (eGFR) is greater than 60 mL/min/1.73 m2; therefore you start her on metformin. She also adopts lifestyle modifications to increase her activity and lose weight. She also is started on an angiotensin-converting enzyme (ACE) inhibitor for her hypertension and a statin for her hypercholesterolemia. She wants to know how much reduction in her A1c she can expect on metformin given as monotherapy and if you think she can get her glucoses under control with this one drug. She also asks if this medicine is likely to cause hypoglycemia.

5.

How much of a reduction in her A1c (in percentage points) can you expect from metformin as monotherapy?2,7,10,11

The typical A1c reduction is 1.5% for patients using metformin as monotherapy, so it would be reasonable to expect her to improve from 7.4% to the target of less than 7%.2,7 According to a 2017 review of drugs for type 2 diabetes, most therapies for diabetes would result in a 0.5% to 1.5% reduction.7 The most effective therapeutic classes (with an expected 1%-1.5% A1c reduction) are the biguanides (metformin), sulfonylureas, TZDs, GLP-1 receptor agonists, and SGLT2 inhibitors7. Other, older therapies do not have as much of an A1c reduction.

Besides possible weight loss, another benefit of metformin is that it typically does not cause hypoglycemia. Its use has, however, been associated with a vitamin B12 deficiency.10 Therefore, “periodic” testing of B12 should be considered, particularly in patients with anemia or symptoms of peripheral neuropathy.10,11

6.

Are there any drug classes for the treatment of type 2 diabetes mellitus that have been shown to reduce cardiovascular disease?

There are new data emerging regarding the cardioprotective effects of SGLT2 inhibitors (specifically with Empagliflozin and Canagliflozin) and the GLP-1 receptor antagonists Liraglutide (LEADER trial). Although SGLT2 inhibitors have some proven efficacy for primary and secondary prevention of cardiovascular endpoints, their cadioprotective effects are most pronounced in patients with underlying CV disease.12,13 Liraglutide has been show more beneficial than other GLP-1 in reducing CV endpoints (CV death, non-fatal MI, or stroke).13,14 Trials are currently underway to investigate the use of drugs from these two classes in combination.

 

Glycemic Control — Improved glycemic control lowers the risk of microvascular complications in patients with type 2 diabetes (figure 1) [1].

Every 1 percent drop in glycated hemoglobin (A1C) is associated with improved outcomes over the long term with no threshold effect. However, as A1C levels decrease below 7 percent, the absolute risk for microvascular complications and the incremental benefit of lowering A1C further has diminishing returns.

Several randomized clinical trials have demonstrated a beneficial effect of intensive therapy on macrovascular outcomes in type 2 diabetes [2,3], with other trials not supporting a beneficial effect [4] and one trial suggesting harm [5].

A reasonable goal of therapy might be an A1C value of ≤7.0 percent (53.0 mmol/mol) (calculator 1) for most patients.

However, target A1C goals in patients with type 2 diabetes should be tailored to the individual, balancing the potential for improvement in microvascular complications with the risk of hypoglycemia and other adverse effects of treatment. Glycemic targets are generally set somewhat higher for older adult patients and those with comorbidities or a limited life expectancy who may have little likelihood of benefit from intensive therapy.

Glycemic goals are discussed in more detail separately. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Glycemic control' and "Treatment of type 2 diabetes mellitus in the older patient", section on 'Controlling hyperglycemia' and "Glycemic control and vascular complications in type 2 diabetes mellitus".)

Cardiovascular risk factor management —Vigorous cardiac risk reduction (smoking cessation; blood pressure control; reduction in serum lipids with a statin; diet, exercise, and weight loss or maintenance; and aspirin when indicated) should be a top priority for all patients with type 2 diabetes.

Aggressive multifactor risk reduction lowers the risk of both micro- and macrovascular complications in patients with diabetes [6,7]

Goals for A1C, blood pressure control, and management of dyslipidemia. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Aspirin' and "Treatment of hypertension in patients with diabetes mellitus" and "Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

DIABETES EDUCATION

igorous cardiac risk reduction (smoking cessation; blood pressure control; reduction in serum lipids with a statin; diet, exercise, and weight loss or maintenance; and aspirin when indicated) should be a top priority for all patients with type 2 diabetes. However, in spite of evidence that aggressive multifactor risk reduction lowers the risk of both micro- and macrovascular complications in patients with diabetes [6,7], a minority of adults with diabetes fully achieve recommended goals for A1C, blood pressure control, and management of dyslipidemia. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Aspirin' and "Treatment of hypertension in patients with diabetes mellitus" and "Management of elevated low density lipoprotein-cholesterol (LDL-C) in primary prevention of cardiovascular disease" and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Multifactorial risk factor reduction'.)

 

 

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Patients with newly diagnosed diabetes, assess

nutrition and weight history,

assessment of physical activity,

cardiovascular risk factors,

history of diabetes-related complications,

diabetic ketoacidosis (DKA) frequency (typically type 1 diabetes),

family history,

current management.

 

Outpatient'

Inpatient

 

microvascular complications are related to duration and degree of hyperglycemia


A growing body of evidence indicates that basal/bolus insulin is the superior approach to managing diabetes on non–critical care hospital services.

In the RABBIT-2 trial, patients with type 2 diabetes mellitus admitted to general medicine services were randomized to a basal/bolus insulin protocol with glulisine (Apidra) dosed at meals and Glarg (Lantus) administered daily for basal insulin or a sliding scale insulin protocol (regular insulin dosed depending on CBG measurements). Glycemic control was significantly better for basal/bolus insulin–managed patients than for sliding scale insulin–managed patients. A basal/bolus insulin protocol study at Carle Foundation Hospital in Urbana, Illinois, documented significant improvements in both glycemic control and hospital length of stay for patients on general medicine. Basal/bolus insulin was compared with sliding scale regular insulin for general surgery patients in the RABBIT-2 Surgery trial, and basal/bolus insulin–managed patients had better blood glc control, fewer surgical morbidities, and shorter stay in the surgical intensive care unit than patients managed with sliding scale insulin.

●If not measured in the past two to three months, we measure A1C (see "Estimation of blood glucose control in diabetes mellitus", section on 'Glycated hemoglobin')

●If not measured in the past one year, we measure:

•Fasting lipid profile

•Liver function tests

•Urine albumin-to-creatinine ratio (spot urine)

•Serum creatinine (with estimated glomerular filtration rate [eGFR])

●In patients with type 1 diabetes we also measure, periodically:

•Serum thyroid-stimulating hormone (TSH)

•Celiac antibodies to screen for celiac disease, which can be asymptomatic [34]

Differentiating the cause — Type 2 diabetes can usually be differentiated from other causes of diabetes based upon the clinical presentation of the patient (table 3). We measure autoantibodies (eg, glutamic acid decarboxylase [GAD]-65, islet tyrosine phosphatase 2 [IA-2], anti-insulin antibodies) and C-peptide level when the diagnosis of type 1 or type 2 diabetes is uncertain by clinical presentation. As examples:

●Catabolic presentation (eg, weight loss, ketonuria)

●Lean body habitus with no features of metabolic syndrome

●Personal history of autoimmune diseases

●Strong family history of autoimmune disease, including type 1 diabetes

●Overweight or obese adolescents or young adults presenting with apparent type 2 diabetes, who actually may have an early presentation of type 1 diabetes

Routine screening for pancreatic cancer is patients with new-onset type 2 diabetes is not recommended but can be considered in atypical patients such as older individuals with lean body habitus especially in the settings of weight loss, abdominal pain or nausea, or abnormal liver tests indicating cholestasis [3]. (See "Epidemiology and nonfamilial risk factors for exocrine pancreatic cancer".)

The etiologic classification of diabetes and testing for specific genetic causes of diabetes (eg, maturity onset diabetes of the young [MODY]) is reviewed separately. (See "Classification of diabetes mellitus and genetic diabetic syndromes".)

Diabetes related-complications — Patients with diabetes require ongoing evaluation for diabetes-related complications. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Diabetes-related complications'.)

 

Management Goals

Management goals should be individualized according to the patient’s age, life expectancy, and comorbid conditions.

ADA recommendations are to maintain fasting glucose levels of 80–100 mg/dL and HgbA1c levels <7%;

The American College of Endocrinology recommends a 2-hour postprandial glucose <140 mg/dL and has set a goal for HgbA1c at <6.5%.

Blood pressure should be maintained below 130/80 mmHg, but the ADA has recently liberalized the systolic goal to 140, and JNC-8 recommends < 140/90 mmHg.

Lifestyle and Self-management

The initial and ongoing evaluation for diabetes includes counseling regarding lifestyle and self-management including

smoking cessation,

goals and motivation, ???

psychosocial issues, and compliance, family support, and self-image.

Every visit should include the following:

  • Weight and BMI

  • Blood pressure measurement

  • Funduscopic examination

  • Basic physical exam concentrating on cardiovascular evaluation

  • Brief skin examination

  • Visual examination of feet

Regular screening and laboratory measurements include the following:

  • A1c level every 3 months (every 6 months if usually well controlled)

  • Verbal or written screen for depression

  • Yearly dilated retinal exam to screen for retinopathy

  • Yearly microalbumin to screen for nephropathy

  • Yearly foot exam including monofilament, vibratory, and evaluation of pulses

  • Yearly fasting lipid profile

  • Yearly electrolytes, BUN, creatinine, and urinalysis

Immunizations should be updated:

  • Influenza yearly

  • Pneumococcus (Pneumovax) once and repeat at age 65

  • Tdap

  • Hepatitis B (most evidence for those aged <60)

Use of guidelines, electronic health records, patient management systems, checklists and questionnaires, standing orders (Table 36-2), and a team approach can increase efficiency and provide more comprehensive care for patients with diabetes.


Standing orders for diabetic patients.

  1. Monitor and record blood pressure in the same arm at each visit.

  2. Measure and record the patient’s weight.

  3. If HbA1c has not been evaluated in the past 6 months, order.

  4. If urinalysis and microalbumin testing have not been done in the past year:

    1. Perform a urine dipstick and record the results on the flowsheet.

    2. Order a urine microalbumin test.

  5. If a lipid profile has not been obtained in the past year, order.

  6. If a dilated eye examination has not been performed in the past year, complete a referral for an ophthalmology examination.

  7. Ask the patient to remove his/her shoes and socks.

    1. Palpate dorsalis pedis and posterior tibial pulses.

    2. Inspect the skin for any skin breakdown.

    3. Record the findings on the patient’s flowsheet.

  8. Check to see if patient has received a pneumococcal vaccine, a dT or Tdap vaccine in the last 10 years, a flu shot for the current season, and completed a hepatitis B series. If patient has not received the flu shot, administer following standard clinic protocol.

(Should be in the ORDERS Section of the Electronic Medical Record.

 

 

Metformin

Titrated to 1000 mg twice daily without side effects. She also modifies her diet and starts an exercise program. Three months later, capillary blood glucose measurements are consistently below 130 mg/dL, and HbA1c improves to 6.0%. Four years later, HbA1c increases steadily to 7.5% despite compliance with diet, exercise, and metformin. Dilated fundoscopy and foot examination are unremarkable, and urine albumin/Cr ratio remains below 30 mg/g.

Initially, HbA1c improves with the addition of glimepiride to metformin. Exenatide is then started 18 months later due to worsening glycemic control. Two years later, the patient returns to discuss treatment options. Despite taking maximal effective doses of metformin (1000 mg BID), glimepiride (8 mg QD), and exenatide (10 μg BID), HbA1c is 8.5%. Fasting glucose measurements fall mostly in the range of 140 to 180 mg/dL, and glucose measurements during the day increase steadily and are often more than 200 mg/dL.