Diabetes Mellitus Type 1: Drug Therapy

A goal of therapy

Glucose

BG fasting/preprandial 90-130 mg/dl (5.0-7.2 mmol/l)
BG 1-2 h postprandial (after meal). <180 mg/dl (<10 mmol/l)
HbA1c <7.5% (up to 6% if there is no risk of frequent hypoglycemia/ hypoglycemia; most guidelines recommend an HbA1c level of less than 7.0%, which not even one in 10 patients achieves in the long term; see Diabetes mellitus type 1/consequential diseases/prognostic factors for details) Hypoglycemia occurs when the patient injects too much insulin before meals or overestimates nighttime requirements.

Other parameters

Parameter State Therapy target
Lipids (blood fats) Patients without microvascular or macrovascular disease.
Patients with microvascular or macrovascular disease.
Patients with triglycerides >1,000 mg/dl
  • Triglycerides acutely < 400 mg/dl (< 10.3 mmol/l),
  • Under continuous therapy < 150 mg/dl (< 3.9 mmol/l).
Blood pressure Patients with arterial hypertension/high blood pressure
  • < 130 mmHg/ < 80 mmHg
Weight BMI
  • ≤ 25 kg/m2

Therapy recommendations

Insulin therapy:

  • Basal-assisted oral therapy (BOT).
  • Supplemental insulin therapy with preprandial (“after meals”) injections without basal insulin (SIT).
    • If necessary, maintain oral antidiabetic agents
  • Conventional insulin therapy (CT)
    • Rigid injection regimen: administration of insulin mixture (usually 1/3 normal insulin, 2/3 intermediate insulin).
    • 2 x daily (morning, evening) ≈ 2/3 of total, 30 min before breakfast,≈ 1/3, 30 min before dinner
      • Morning: normal insulin (covering breakfast), intermediate insulin (for baseline needs + lunch).
      • Evening: normal insulin (covering dinner), intermediate insulin (basic needs).
    • No flexibility
    • Indications: elderly and dependent patients (due topoor compliance).
  • Intensified conventional insulin therapy (ICT), first-line therapy.
    • Basal insulin level: coverage of basal requirement via long-acting insulin/intermediate insulin (dose is determined individually; administration late in the evening, possibly additionally early in the morning).
    • Meal-related insulin requirement: meal-adapted injection of alteinsulin (depending on appetite, blood glucose, time, physical exertion) by well-trained patient.
  • Intensified insulin therapy:
    • At least 3 insulin injections per day.
    • Substitution as follows:
      • Basal insulin level: basal insulin requirement with long-acting basal insulin/delayed-release insulin (1 x /d).
      • Meal-related insulin requirement: prandial (meal-related) insulin requirement with short-acting “bolus insulin”
    • Implementation with: Insulin syringe, insulin pens or insulin pumps.
    • Flexible insulin doses depending on the situation.
  • Insulin pump therapy (PT)
    • Basal insulin level: delivery of a continuous amount of alte insulin s.c. as basal requirement.
    • Meal-related insulin requirement: bolus altinsulin at meals; adjust dose to current blood glucose level and energy content of food
    • Indications: frequent hypoglycemia (low blood glucose), highly fluctuating blood glucose levels, poorly adjustable diabetes mellitus during pregnancy (gestational diabetes), planned pregnancy in type 1 diabetic women.
    • Meanwhile, there is a “closed loop” (a closed circuit) of sensor-based glucose measurement and insulin pump. Here, insulin delivery is automatically controlled by real-time glucose measurement (“artificial pancreas“/”artificial pancreas”).The quality of the therapy is judged, among other things, by the “time in range” (TIR). This indicates the proportion of time during the course of the day that glucose levels are within the desired range of 70-180 mg/dl. The following are the results over the course of the study:
      • TIR values averaged 61% (verum group) and 59% (control group) at baseline; 6 months after therapy, values increased by an average of 10 percentage points to 71% in the verum group and remained largely unchanged in the control group.
      • Reduction of HbA1c (long-term glucose) and hyperglycemia and hypoglycemia times (hyperglycemia and hypoglycemia).

    Patients receiving an insulin pump have a lower risk of mortality than patients who inject themselves

Patient recommendation

  • Regularly changing the injection site avoids lipodystrophy (fat distribution disorder; fat shrinkage).

Notice:

  • Patients with latent autoimmune diabetes in adulthood (LADA) are treated largely like patients with type 2 diabetes mellitus, but usually need insulin earlier than type 2 diabetics without antibodies.

Important facts

  • Daily insulin requirement about 0.5-1.0 I.U./kg/die (average ≈ 40 I.E./d in insulin deficiency).
  • 1 bread unit (BE) ≡ amount of food containing 12 g of carbohydrate; 1 BE ≡ 2 I:E: insulin: 1 IU at noon and 1.5 IU in the evening Calculation of the amount of insulin needed = amount of bread units per meal multiplied by the so-called BE factor; BE factor ≡ amount of insulin needed by the patient to break down one bread unit without a rise in blood glucose
  • 1 I.U. normal insulin lowers blood glucose (Bz) by ≈ 30 mg%.
  • Dose adjustment insulin amount: (current Bz minus target (120 mg%)) divided by 30, the result multiplied times (quotient: daily insulin requirement divided by 40).
  • Caveat: 1 ml of normal insulin ≡ 40 I.E:/ml; insulin for the pen: 100 I.I./ml!

Other topics (see below)

  • Notes on insulin allergy (see below).
  • Therapy recommendations in different situations (see below).
  • Notes on insulin concomitant therapy with GLP-1 analogues (such as liraglutide) or SGLT inhibitors (such as dapagliflozin and sotagliflozin) (see below) [reports from current research].

Active ingredients (main indication)

Insulin

Active ingredient Onset of action Maximum effect Duration of action Indications Special features
Short-acting insulins
Normal insulin (= old insulin) 15-30 min 1-3 h 5-8 h ICT, PT, i.v. therapy <30 min injection-eating interval
Insulin analoguesInsulin lisproInsulin aspartInsulin glulisine 5-15 min 1 h 2-3 h ICT No splash-eat distance
Delayed-release insulin
Intermediate insulin 45-90 min 4-10 h Max 24 h Type 2 therapy 30-60 min spray-eat interval
Long-term insulin 2-4 h 7-20 h 28-36 h ICT 30-60 min spray-eat interval
Insulin analoguesInsulin glargineInsulin detemir 2-4 h 20 h/> 24 h ICT 30-60 min injection-eating interval

Lower risk of hypoglycemia;better and lower-risk metabolic control possible

Combination insulins
Depending on the exact compositionof normal and delayed-release insulin. CT < 30 min spray-eat interval

Mode of action

Replacement of the lack of endogenous insulin:

  • → glycogen synthesis, lipid synthesis, protein biosynthesis.
  • → glycogenolysis ↓, gluconeogenesis ↓, proteinolysis ↓, lipolysis ↓

Add-on therapy for type 1 diabetes

Incretin mimetics (GLP-1 receptor agonists).

Active ingredient Special features
Liraglutide Meal-independent subcutaneous.

In 2014, a fixed combination with insulin degludec was approved

  • Mechanism of action: Incretin mimetics increase insulin secretion; incidentally, they promote faster satiety.
  • Side effects: gastrointestinal (nausea, diarrhea, vomiting); abdominal pain, reduced appetite.
  • Note: The incretin mimetic liraglutide (analogue of the hormone incretin (GLP-1)) exhausted beta cells (“burnout” of beta cells) in the long term in an animal study.
  • Decrease in body weight; marginally better adequate control of type 1 diabetes; add-on therapy did not result in more hypoglycemia

Gliflozine (SGLT-2 inhibitors; SGLT-2 blockers).

Active ingredient Special features
Dapagliflozin Patients with chronic renal insufficiency benefit significantly. In severe hepatic impairment, therapy should be started at 5 mg/d and then possibly increased to 10 mg. Insulin doses should be continuously optimized with dapagliflozin!
Sotagliflozin Combined SGLT1 and -2 inhibitor.

The use of sotagliflozin is not recommended in moderate and severe hepatic impairment.

  • Mode of action: Selective inhibition of sodium-glucose cotransporter 2 (SGLT-2) by about 40-50% → inhibition of renal glucose absorption (glucosuria in healthy subjects: 60-70 g/d; in diabetics 80-120 g/d) → blood glucose reduction (HbA1c reduction), weight loss, blood pressure reduction.
  • The lower the renal function, the lower the effect of SGLT-2 inhibitors: Not indicated in renal function impairment; with a GFR of 30-60 ml/min, only an HbA1c reduction of 0.4 % is to be expected
  • Indication: type 1 patients with a BMI ≥ 27
  • Contraindications: Hypersensitivity to the active ingredient; gravidity (because of toxicity in animal studies).
  • SGLT-2 inhibitors are not recommended in volume deficiency or diuretic therapy.
  • Side effects: gastrointestinal (nausea), urinary tract infections, genital infections (vulvitis and vulvovaginitis in women and balanitis in men), back pain, dysuria, polyuria, dyslipidemia.
  • Patients should measure their own ketone levels
  • U.S. Food and Drug Administration warns of possible occurrence of severe ketoacidosis during therapy with SGLT2 inhibitors such as canagliflozin, dapagliflozin, and empagliflozin
  • AkdÄ Drug Safety Mail | 07-2017|: Information of the BfArM on SGLT-2 inhibitors: possibly increased risk of lower limb amputations.The U.S. Food and Drug Administration (FDA) concludes in a new assessment of the antidiabetic drug that the risk of amputation under treatment with canagliflozin is not as high as previously thought after all.
  • Dapagliflozin: decrease in body weight; little better adequate control of type 1 diabetes; patients had increased risk of diabetic ketoacidosis; increase in genital infections (already known with SGLT inhibitor therapy in type II diabetes.

Therapy in special situations

Physical activity

Sports and heavy physical work lead to increased uptake of glucose by muscle cells whereas this is largely insulin independent. Therefore, depending on the intensity of the activity, insulin doses may need to be reduced by up to 50% before a planned activity, or 2-4 additional carbohydrate servings (bread units; BE) may need to be consumed. After such activity, glucose uptake and burning by muscles may be maintained for hours independent of insulin, so the insulin dose must be adjusted. To avoid exercise-induced hyper- or hypoglycemia (high and low blood glucose), type 1 diabetics should:

  • Measure blood glucose levels before, during and after exercise.
  • Delay start of exercise if blood glucose level is above 14 mmol/l (250 mg/dl) or below 5.5 mmol/l (100 mg/dl)
  • Inject insulin into an area not stressed by physical activity
  • If necessary, supply additional carbohydrates when insulin dose adjustment is no longer possible

Acute or chronic infections

These increase the insulin requirement due to the catabolic state, which thus significantly complicates diabetes control. In such a case, the insulin dose must be gradually increased depending on blood glucose levels to be able to maintain blood glucose levels at least in a range of 8.3-11.1 mmol/l (150-200 mg/dl).Not infrequently, an additional requirement of 50-100% is necessary for this. Complete normalization of blood glucose is almost never successful and is not necessary in such a situation. As the infection subsides, the insulin dose must be gradually reduced again. Under no circumstances should the mistake be made of not administering insulin at all if the patient refuses to eat due to the illness. This is a common mistake that patients and relatives make and should be taught separately in training sessions.

Insulin Allergy

  • In 95% of cases with suspected insulin allergy, no allergic component is the cause of symptoms
  • Measures to be taken in cases of insulin allergy (modified from Jaquier et al. 2013).
    • Severity: mild
      • Investigations: Rule out defective needles; confirm response to insulin.
      • Measures: replace needles and/or insulin preparation if necessary; antihistamine if needed.
    • Severity: moderate
    • Severity: severe or persistent.
      • Investigations (in addition to above):
        • Prick or intradermal skin test.
        • C1 inhibitor
        • Complement factors
        • Exclude viral and bacterial infections as a cause of urticaria (hepatitis B, CMV, EBV).
        • If necessary, dermatologist / rheumatologist / immunologist / consult.
      • Measures:
        • H1 and H2 antihistamines (loratadine + ranitidine).
        • If necessary, insulin i.v. briefly
        • Insulin pump therapy with or without hydrocortisone.
        • Hyposensitization
        • Systemic steroids; leukotriene receptor antagonist; omalizumab (anti-IgE monoclonal antibody); systemic immunosuppression.
        • Pancreas transplantation

Perioperative care

Surgical procedures in diabetic patients should be planned with close coordination of the surgeon, anesthesiologist, and internist. The following approach has proven effective in insulin-injecting diabetics:

  • Surgery as early in the day as possible
  • Blood glucose monitoring every 1-2 hours (target: 6.7-11.1 mmol/l/120-200 mg/dl)
  • If necessary, glucose infusion/insulin i.v. (depending on the clinic’s internal scheme).
  • Serum potassium control
  • Postoperatively return to the original treatment regimen as soon as the patient can eat

Pregnancy

Pregnancy in type 1 diabetic women requires careful planning and strict adherence to therapeutic measures. For diabetic women of childbearing potential, normalization of HbA1c and intensified insulin therapy should be sought. Especially at conception-preferably before conception-and in the first trimester (third trimester of pregnancy), metabolism must be very well adjusted, otherwise the risk of fetal malformations is increased four- to tenfold!

Therapy of “hypercholesterolemia” for secondary and primary prevention

An indication for statin therapy exists (according to American College of Cardiology and American Heart Association guidelines; November 2013) for:

  • Patients with cardiovascular disease regardless of LDL levels.
  • Individuals with LDL levels from ≥ 4.9 mmol/l (≥ 190) mg/dl
  • Diabetics aged 40-75 years
  • Patients with a 10-year cardiovascular risk of 7.5% or more and an LDL level of 170 mg/dl or more

Specific therapeutic measures for diabetic sequelae

See under the topics of the same name: