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Guidelines For Management Of Type 1 And Type 2 Diabetes Mellitus

INTRODUCTION

Diabetes mellitus is a metabolic disease that requires ongoing medical attention and family support in order to reduce complications and maintain glycemic control. Patients must be educated about self-management and support in order to reduce the risk of long-term consequences and avoid acute ones.

TREATMENT GOALS TO PREVENT COMPLICATIONS AND OPTIMIZE THE QUALITY OF LIFE

Medical Nutrition Therapy
For every diabetic patient, a customized medical nutrition therapy approach is best. Although a licensed dietician is required to provide advise, a thorough talk about diet with the treating physician can be very beneficial if such facilities are not accessible. All individuals who are overweight and obese with type 2 diabetes and prediabetes should aim for a suggested weight loss (>5%) through calorie restriction and lifestyle changes (Table 1).
Table 1. Treatment options type 2 diabetes mellitus who are overweight or obese.

 

BMI category (kg/m2)

Treatment

25.0–26.9

(or 23.0– 26.9*)

27.0–29.9

30.0–34.9

(or 27.5– 32.4*)

35.0–39.9

(or 32.5– 37.4*)

≥40 (or

≥37.5*)

Diet, physical activity

+

+

+

+

+

Pharmacotherapy

 

+

+

+

+

Metabolic surgery

 

 

+

+

+

*Cut-off for Asians.  +Treatment may be indicated for selected motivated patients.

Since there is no one optimal dietary distribution of calories across proteins, lipids, and carbs, meal plans should be customized while keeping in mind metabolic objectives and total caloric intake. Complex, high-fiber sources of carbohydrates should be consumed, such as fruits, vegetables, whole grains, legumes, and some dairy products. To improve glycemic control, patients with type 1 and type 2 diabetes receiving insulin therapy should be taught how to count carbohydrates and how to calculate insulin dosage at mealtimes by taking protein and fat content into account.

The most effective way to enhance glycemic control is to eat a balanced diet. Certain diets, such as the Paleo and ketogenic diets, can only be followed for brief periods of time under close supervision and in institutional settings, and they must be well watched for any negative consequences.

Adult men and women are allowed to consume one drink and two drinks, respectively. However, alcohol reduction must be recommended for people with fatty livers.

Exercise

The best exercise for patients with diabetes is a combination of aerobic and resistance training. The muscle mass increases with resistance training which contributes to blood glucose uptake without altering the muscle’s intrinsic capacity to respond to insulin. The aerobic exercises on the other hand enhance glucose uptake via an enhanced insulin action, and this is independent of changes in muscle mass or aerobic capacity. 

Pharmacological Therapy for Type 1 Diabetes

Insulin for Type 1 Diabetes Mellitus

People with type 1 DM should be continued on basal bolus insulin therapy. Insulin requirements are estimated based on weight. The typical doses range from 0.4 units/kg/day to 1.0 units/kg/day. Higher amounts of insulin need to be given during puberty, pregnancy, and medical illness. The insulin dose can be divided conventionally into one half as prandial for mealtime glucose and the rest as basal to control glycemia in the periods between meal absorption.  

Non-insulin Treatment for Type 1 Diabetes Mellitus

Metformin (Not approved): There are some studies with metformin where its addition helped in causing body weight and lipid levels reductions to a small extent but did not improve A1c.  Presently metformin is not approved to use in type 1 diabetes mellitus.

Pramlintide: Pramlintide is an analogue of naturally occurring β-cell peptide amylin and is approved for use in adults with type 1 diabetes. Studies showed variable reductions of A1c (0–0.3%) and body weight (1–2 kg) with the addition of pramlintide to insulin.

GLP1 Agonists (Not Approved): The glucagon-like peptide 1 (GLP-1) receptor agonists liraglutide and exenatide added to insulin therapy have shown small reductions in A1c about 0.2% compared with insulin alone in people and also reduced body weight by 3 kg.
SGLT2 Inhibitor (Not Approved Presently): Sodium–glucose cotransporter 2 (SGLT2) inhibitor added to insulin therapy has shown improvements in A1c and body weight when compared with insulin alone, but the risk of ketoacidosis is very high.7 Sotagliflozin which is a dual SGLT1/2 inhibitor, is currently under consideration by the FDA.

Surgical Treatment for Type 1 Diabetes Mellitus
Pancreas and Islet Transplantation
Pancreas and islet transplantation is a surgical option to normalize glucose levels but is associated with problems like lifelong immunosuppression and recurrence of autoimmune islet destruction. This candidates for pancreas transplantation include patients with type 1 diabetes undergoing simultaneous renal transplantation, following renal transplantation, or those who have recurrent ketoacidosis or severe hypoglycemia despite intensive glycemic management.
Pharmacotherapy for Type 2 Diabetes Mellitus
Metformin
It is one of the preferred initial pharmacologic agents for the treatment of type 2 diabetes as per all international and national guidelines. The gastrointestinal side effets are common and are dose-dependent and do improve with time. The dose reduction may be needed for some patients because of these side effects. It is not approved for use in patients with an eGFR < 30 ml/min/1.73 m2 and dose reduction should be considered when the eGFR is <45 ml/min/1.73 m2. It has high efficacy, low cost, minimal hypoglycemia risk when used as monotherapy, and the potential for some weight loss. This makes it the preferred agent of choice for patients with type 2 diabetes mellitus. There is no conclusive evidence on reduction of CVD but as compared to sulfonylureas, the risk for cardiovascular mortality is lower. There is a risk of vitamin B12 deficiency with long-term use and patients need to be supplemented with vitamin B12 if they have a deficiency or symptoms of peripheral neuropathy.11 The risk of lactic acidosis is very miniscule and is seen mostly within the setting of severe illness or acute kidney injury.
SGLT2 Inhibitors
SGLT2 inhibitors are one of the latest oral antidiabetic medications that reduce plasma glucose by enhancing urinary excretion of glucose. All SGLT2 inhibitors have the advantage of reducing weight and blood pressure.  

Figure 1. Glucose lowering in type 2 diabetes mellitus

Anti-diabetic drugs (OADs) like sulfonylureas and insulin the risk can be increased. Empagliflozin, dapagliflozin and canagliflozin have cardiac and renal benefits in patients with established or at high risk of ASCVD. The lower approved eGFR cut- off for the use of SGLT2 inhibitors 45 mL/min/1.73 m2 but latest data has shown efficacy till eGFR of 30 mL/min/1.73 m2 along with glycemic control. They are associated with increased risk for mycotic genital infections (mostly vaginitis in women, balanitis in men).
SGLT2 inhibitors can cause diabetic ketoacidosis but it can be avoided by not using it during stress states and to not use it in other types of diabetes. CANVAS study showed that canagliflozin is associated with increased risk for lower limb amputations and fractures whereas CREDENCE study didn’t indicate any increased risk for amputations and fractures. It is uncertain whether amputation and fractures are class effects.

GLP-1 Receptor Agonists
These medications help in stimulating insulin secretion and reducing glucagon secretion in a glucose-dependent manner, improve satiety and promote weight loss. The duration of action is related to the structural differences among GLP-1 receptor agonists, and their efficacy, weight losing effects, side-effect profile and cardiovascular benefit is dependent on formulation and dosing.
There are once weekly formulations like dulaglutide, exenatide extended-release and semaglutide  and daily formulations like liraglutide. GLP-1 receptor agonists have high glucose-lowering efficacy, but with variation within the drug class. The weight reduction with all GLP-1 receptor agonists ranges from about 1.5 kg to 6.0 kg over about 6–7 months of therapy.
GLP-1 receptor agonists delivered by subcutaneous injection but oral formulations are under research.
Liraglutide, semaglutide and dulaglutide have been shown to improve cardiovascular outcomes. The common side effects are nausea, vomiting and diarrhea, though these tend to lessen over time. The patients are told to avoid heavy and fatty meals when they start taking it as it may exacerbate nausea and vomiting. GLP-1 receptor agonists when used with metformin or alone have a minimal risk for hypoglycemia, but when combined with insulin and sulfonylureas, the risk increases. An increased risk of gallbladder events is seen. Semaglutide was shown to be with increased retinopathy complications in the SUSTAIN 6 trial, and it is seen in those with baseline retinopathy who had rapid improvement of glycemic control. GLP-1 receptor agonists have not been shown to substantially increase the risk for pancreatitis, pancreatic cancer or bone disease.

DPP-4 Inhibitors
DPP-4 inhibitors are oral medications which agument the increase in insulin secretion by blocking the DPP-4 enzymes and reduce glucagon secretion in a glucose-dependent manner. They have moderate glucose-lowering efficacy. DPP-4 inhibitors are weight neutral and have minimal risk of hypoglycemia when used as monotherapy but when used in combination with agents like sufonyureas and insulin, the risk increases. The dose of DPP-4 inhibitor needs to be adjusted based on renal function; linagliptin is the exception as it has minimal renal excretion. Teneligliptin also does not need dose adjustment based on renal function. Some causes of pancreatitis have been reported but most of the real world studies have not confirmed that some studies have also shown increased musculoskeletal side effects. DPP4 inhibitors are cardioneutral though some studies showed increased hospitalization for heart failure for saxagliptin.

Thiazolidinediones
Thiazolidinediones (TZDs) (pioglitazone) are oral medications that increase insulin sensitivity and are of high glucose-lowering efficacy. They are most useful for young individuals who are not overweight or obese. Thiazolidinediones increase HDL-cholesterol, and pioglitazone has been shown to reduce cardiovascular endpoints, and hepatic steatohepatitis. Thiazolidinediones have good glycemic durability. However, the safety concerns regarding fluid retention and congestive heart failure, weight gain, bone fracture and, possibly, bladder cancer have limited their extensive use.
Sulfonylureas
Sulfonylureas are inexpensive medications with good glycemic efficacy and they lower glucose by stimulating insulin secretion from pancreatic beta-cells. Sulfonylureas have demonstrated good effect on reduction in microvascular complications in the UKPDS and ADVANCE trials. Sulfonylureas cause weight gain and increase the risk for hypoglycemia though lower than seen with insulin. Glibenclamide has a higher risk of hypoglycemia compared with other sulfonylureas. Glipizide, glimepiride and gliclazide may have a lower chance for hypoglycemia compared with other sulfonylureas. Glibenclamide abolishes ischemic preconditioning and should be avoided. The other sulfonylureas in use are cardioneutral. Greatest caution is warranted for people at high risk of hypoglycemia, such as older patients and those with CKD. Gliclazide is approved for use across all stages of diabetic kidney disease.
Insulin
‘Human’ insulins (NPH, regular [R], and premixed combinations of NPH and R) are recombinant DNA-derived human insulin, while insulin analogues have been designed to change the onset or duration of action. Insulin lowers glucose in a dose-dependent manner, to almost any glycemic target . There is an increased risk of hypoglycemia with the use of insulin and also other disadvantages include weight gain and the need for injections, frequent titration for optimal efficacy and glucose monitoring. The intermediate- and long-acting insulins differ in timings of onset, durations of action and risks of hypoglycemia. The treating physician should ensure whether insulin administration, rotation and storage are correctly followed and also check for any hypertrophy or lipoatrophy at insulin injection sites at each visit.

Basal Insulin
Basal insulins are longer-acting insulin which cover the body’s basal metabolic insulin requirement (Fig. 2). There are various options which include once- or twice- daily administration of intermediate-acting NPH or detemir insulin and the once- daily administration of glargine (U100 or U300) or degludec (U100 or U200). The advantage of long-acting insulin analogues like degludec, glargine [U100 and U300 and detemir are that they have a modestly lower absolute risk for hypoglycemia compared with NPH insulin, but the cost is more. Biosimilar formulations are also available for glargine and have shown similar efficacy with lower cost. Insulin has not been shown to reduce the risk for CVD, but data suggest that glargine U100 and degludec do not increase the risk for MACE.


Figure 2. Algorithm for titration of insulin.

The advantage of glargine (U300) are available that allow injection of a reduced volume and is convenient for patients on higher doses. Not all patients have their blood glucose adequately controlled with basal insulin. The patients require intensification of therapy with prandial insulin if glucose values are not controlled with basal insulin therapy.

Prandial Insulin Formulations

The patients who are not adequately controlled (Table 2) with basal insulin therapy require intensification with meal-time administration of short- or rapid-acting or ultrarapid-acting insulin formulations. There are various options like human regular insulin, different analogues (aspart, glulisine and lispro), formulations (faster insulin aspart, lispro U200). The rapid-acting insulin analogues have a modestly lower risk for hypoglycemia, provide more flexibility as compared with human regular insulin but the cost is higher. Various premixed formulations of human and analogue insulins are available and continue to be widely used in India as patients comply better with them because of one type of insulin with lesser prick (Fig. 2).

Table 2. Glycemic targets as recommended by various organisations

 

ADA 2019

IDF 201737

RSSDI 201738

HbA1c

<7%

<7%

<7%

HbA1c (if hypoglyce- mia can be avoided)

6.5%

Lower HbA1c target

Lower HbA1c target

HbA1c (h/o severe hypoglycemia, h/o advanced micro- or macrovascular compli- cations, comorbidities)

<8%

7.5–8%

Higher HbA1c target

Other Glucose-lowering Medications

Other oral glucose-lowering medications are meglitinides, α-glucosidase inhibitors, colesevelam, quick-release bromocriptine, pramlintide.

α-Glucosidase Inhibitors: The digestion of complex carbohydrates can be slowed by inhibiting amylases and glucosidases can reduce post-prandial hyperglycemia, particularly in individuals consuming a high-starch diet like white rice. Reversible competitive inhibitors of the brush-border α-glucosidases are acarbose, miglitol and voglibose. These can cause flatulence and diarrhea as side effects.

Hydroxychloroquine (HYQ): Hydroxychloroquine has been approved by DCGI in the management of T2DM in India. It has a modest effect on reducing A1c along with the reduction of pro-inflammatory markers. It increases adiponectin levels. It inhibits insulin degradation, reduces inflammation, preserves beta-cell reserve and improves insulin sensitivity.

  • Preprandial Capillary Plasma Glucose 80–130 mg/dL
  • Peak Postprandial Capillary Plasma Glucose <180 mg/dL

  The early introduction of insulin should be considered in cases with evidence of ongoing catabolism (weight       loss), symptoms of hyperglycemia, or when HbA1c levels are >10% or blood glucose levels are ≥300 mg/dL.
   Dual therapy can be initiated in patients with newly diagnosed type 2 diabetes who have A1c ≥1.5% above         their glycemic target.
   A patient-centered approach should be used to guide the choice of pharmacologic agents (Table 3).
   Table 3. RSSDI has devised a therapeutic wheel for treatment of diabetes.

OBESITY MANAGEMENT BEYOND LIFESTYLE INTERVENTION

Medications for Weight Loss

Several medications and medication combinations approved for weight loss have been found to improve glucose control in people with diabetes (Table 1).

Liraglutide, is also approved as an antiobesity medication at a higher dose. In India liraglutide, orlistat and lorcaserin (soon to be launched) are available for the treatment of obesity. Metabolic surgery is highly effective in improving glucose control and often produces disease remission. The effects are sustained for at least 5 years but some weight gain can happen after 3 years. The number of glucose- lowering medicatons needed to achieve glycemic targets is reduced.

Adverse effects of bariatric surgery vary by the procedure which includes surgical complications (e.g. anastomotic or staple line leaks, gastrointestinal bleeding, intestinal obstruction, the need for re-operation). The late metabolic complications include protein malnutrition, mineral deficiency, vitamin deficiency, anemia, hypoglycemia and gastroesophageal reflux.43 People with diabetes presenting for metabolic surgery have been found to have increased rates of depression and other major psychiatric disorders. 44 These factors should be assessed pre-operatively and during follow-up. Metabolic surgery should preferably be performed in high-volume centers with multidisciplinary teams that are experienced in the management of diabetes and gastrointestinal surgery. Long-term lifestyle support and routine monitoring of micronutrient and nutritional status must be provided to patients after surgery.

RECENT UPDATES IN THE MANAGEMENT OF DIABETES
Closed Loop Insulin Delivery
Closed-loop insulin delivery or commonly called artificial pancreas, is an emerging therapeutic approach for people with type 1 diabetes. It is a medical device consisting of a linked continuous glucose monitor and an insulin pump. Wireless communication facilitates real-time feedback between glucose levels and insulin delivery, similar to that presented by the β-cell. Insulin delivery is modulated at intervals of 1–15 minutes, depending on interstitial glucose levels.
Closed-loop systems can be insulin-only or bi-hormonal which include both insulin and glucagon. A hybrid, closed-loop approach can be used which includes manual meal-time adjustment and prandial insulin boluses by the user to overcome the delay in insulin action.
Inhaled Insulin: Exubera®, containing rapid-acting insulin in powder form, has been studied extensively in patients with type 1 and type 2 diabetes mellitus. It was approved by the FDA in 2006 and was withdrawn in 2007.
Afrezza is newer, non-invasive, rapid-acting inhaled human insulin approved for adults with either T1DM or T2DM by FDA in June 2014.
Smart Insulin
Smart insulins also called glucose response insulins are currently being developed to prevent hypoglycemia and glycemic variability.

CONCLUSION
The mainstay of diabetes treatment is a balanced diet and exercise individualized as per patient’s needs.
The pharmacological therapy should be patient-centered and decided on the basis of individualized needs and targets.

REFERENCES

1. Introduction: Standards of Medical Care in Diabetes 2019. Diabetes Care. 2019;42 (Suppl 1):S1–S2

2. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2019 American Diabetes Association. Diabetes Care. 2019;42(Suppl 1):S90–S102

3. Peters A, Laffel L (Eds.). American Diabetes Association/JDRF Type 1 Diabetes Sourcebook Alexandria, VA, American Diabetes Association, 2013.

4. MengH, Zhang A, Liang Y, et al. Effect of metformin on glycaemic control in patients with type 1 diabetes: a meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2018;34:e2983.

5. Edelman S, Garg S, Frias J, et al. A doubleblind, placebo-controlled trial assessing pramlintide treatment in the setting of intensive insulin therapy in type 1 diabetes. Diabetes Care. 2006;29:2189– 2195.

6. Wang W, Liu H, Xiao S, et al. Effects of insulin plus glucagon-like peptide-1 receptor agonists (GLP-1RAs) in treating type 1 diabetes mellitus: a systematic review and meta-analysis. Diabetes Ther. 2017;8:727– 738.

7.Dandona P, Mathieu C, Phillip M, et al.; DEPICT-1 Investigators. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:864–876.

8. Robertson RP, Davis C, Larsen J, et al; American Diabetes Association. Pancreas and islet transplantation in type 1 diabetes. Diabetes Care. 2006;29:935.

9. Imam TH. Changes in metformin use in chronic kidney disease. Clin Kidney J 2017;10:301–304.

10.Griffin SJ, Leaver JK, Irving GJ. Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia 2017;60:1620–1629.

11. Aroda VR, Edelstein SL, Goldberg RB, et al. Long-term metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab 2016;101:1754–1761.

12. Zhang X-L, Zhu Q-Q, Chen Y-H, et al. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc 2018;7:e007165.

13. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–657

14. Karagiannis T, Liakos A, Bekiari E, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and metaanalysis of randomized controlled trials. Diabetes Obes Metab 2015;17:1065–1074.

15. Zaccardi F, Htike ZZ, Webb DR, et al. Benefits and harms of once-weekly glucagon-like peptide-1 receptor agonist treatments: a systematic review and network meta- analysis. Ann Intern Med 2016;164:102–113.

16. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322.

17.   Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–1844.

Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular 





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